Review Article Synthesis and Structural Activity...

Review ArticleSynthesis and Structural Activity Relationship Study ofAntitubercular Carboxamides

D I Ugwu1 B E Ezema1 F U Eze1 and D I Ugwuja2

1Department of Pure and Industrial Chemistry University of Nigeria Nsukka 410002 Nigeria2Department of Chemical Sciences Federal University Wukari Nigeria

Correspondence should be addressed to D I Ugwu izuchukwuugwuunnedung

Received 21 August 2014 Revised 21 November 2014 Accepted 30 November 2014 Published 30 December 2014

Academic Editor Arie Zask

Copyright copy 2014 D I Ugwu et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The unusual structure and chemical composition of the mycobacterial cell wall the tedious duration of therapy and resistancedeveloped by the microorganism have made the recurrence of the disease multidrug resistance and extensive or extreme drugresistanceThe prevalence of tuberculosis in synergy with HIVAIDS epidemic augments the risk of developing the disease by 100-fold The need to synthesize new drugs that will shorten the total duration of effective treatment andor significantly reduce thedosage taken under DOTS supervision improve on the treatment of multidrug-resistant tuberculosis which defies the treatmentwith isoniazid and rifampicin and provide effective treatment for latent TB infections which is essential for eliminating tuberculosisprompted this review In this reviewwe considered the synthesis and structure activity relationship study of carboxamide derivativeswith antitubercular potential

1 Introduction

Tuberculosis is an infectious disease caused by Mycobacter-ium tuberculosis which most commonly affects the lungsThe M tuberculosis complex is a set of evolutionary closelyrelated slow growing mycobacterial species all containingthe mobile insertion sequence IS6610 in their genome andcausing TB disease in humans and other mammals It istransmitted from person to person via droplets from thethroat and lungs of people with the active respiratory diseaseIn healthy people infectionswithMycobacterium tuberculosisoften cause no symptoms since the personrsquos immune systemacts to ldquowall offrdquo the bacteria The symptoms of active TBof the lung are coughing sometimes with sputum or bloodchest pains weakness weight loss fever and night sweats[1] TB is a worldwide pandemic [2] and still remains oneof the foremost among infectious diseases in the worldcausing the maximum number of deaths due to the spreadof single microorganisms [3] Of the new TB cases reported95 occur in developing countries every year Currentlyamong the infected individuals approximately eight milliondevelop active TB and almost two million die from thediseases [4] The World Health Organization has expressed

concern over the emergence of virulent drug-resistant strainsof TB and is calling for measures to be strengthened andimplemented to prevent the global spread of these deadlyTB strains The unusual structure and chemical compositionof the mycobacterium cell wall and effective TB treatmentis difficult which makes many antibiotics ineffective andhinders the entry of drugs Multidrug resistance tuberculosis(MDR-TB) defined as resistance to at least isoniazid andrifampicin [5] is a serious threat to tuberculosis controland prevention Isoniazid blocks the biosynthesis of mycolicacids the essential components of mycobacterial cell walland is believed to be oxidized by catalysed peroxidase (KatG) to the active form [6] Mutations in the Kat G and theInh A genes are associated with 70ndash80 of INH-resistantM tuberculosis isolate [7] Resistance to rifampicin has beenassociated with mutations in the 81 bp core region of therpoB gene encoding the 120573-subunit of RNA polymerase [8 9]in over 90 cases The development of resistance by Mtuberculosis to the commonly used antitubercular drugsnecessitates a longer duration of therapy The emergenceof multidrug resistance has forced the development of newstructural classes of antitubercular agents with several ofthem showing promising activity againstM tuberculosis [10]

Hindawi Publishing CorporationInternational Journal of Medicinal ChemistryVolume 2014 Article ID 614808 18 pageshttpdxdoiorg1011552014614808

2 International Journal of Medicinal Chemistry

The tedious duration of therapy and resistance developedby the microorganism has made the recurrence of thedisease especially as MDR-TB and XDR-TB a globalchallenge in tuberculosis chemotherapy [11] XDR-TB isextensive or extreme drug resistance is MDR-TB that isalso resistant to three or more of the six classes of secondline drugs The increase in TB incidence during recentyears is largely due to the prevalence of TB in synergy withhuman immunodeficiency virus (HIVAIDS) epidemicwhich augments the risk of developing the disease by100-fold where 31 of new TB cases were attributed to HIVcoinfection and emergence of MDR-TB and XDR-TB strainsThe treatment of MDR-TB and XDR-TB has become a majorconcern worldwide The occurrence of TB is linked to densepopulation poor nutrition and poor sanitation Observedtreatment short-course (DOTS) strategy constitutes thecornerstone of the current protocol for the control of TB [12ndash19] Currently the recommended standard chemotherapeuticregimen for TB treatment is prescribed under DOTS Thechemotherapeutic regimen consists of an initial 2-monthphase of treatment with isoniazid (INH) rifampicin (RIF)pyrazinamide (PYR) and ethambutol (ETH) followed bya continuation phase of treatment lasting for 4 monthswith isoniazid and rifampicin Poor patience compliancecan promote the emergence of drug resistance and this isparticularly true in TB chemotherapy [20] In the last fortyyears only a few drugs have been approved by the Foodand Drug Administration (FDA) to treat TB reflectingthe inherent difficulties in discovery and clinical testing ofnew agents and lack of pharmaceutical industry researchin the area There is unequivocal need for new drugs thatshould show improvement over the existing regimens in thefollowing areas (a) shortening the total duration of effectivetreatment andor significantly reducing the total numberof doses needed to be taken under DOTS supervision(b) improving the treatment of MDR-TB which cannotbe treated with INH and RIF andor (c) providing moreeffective treatment of latentdormant TB infection whichis essential for eliminating tuberculosis [21] Recentlybedaquiline formerly known as TMC 207 was approvedby United State Food and Drug Administration for thetreatment of adult with pulmonary multidrug resistancetuberculosis when an effective treatment regimen cannototherwise be provided [22] It has no cross resistance to theavailable tuberculosis agents Bedaquiline is marketed asSIRTURO and chemically known as (1R2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthal-enyl)-1-phenyl-2-butanol Though this drug has goodantitubercular activity it needs 24 weeks of treatment therebyencouraging the development of resistance specie arisingfrom noncompliance to prescription and it has also beenshown to cause adverse effects like hemoptysis and anorexia[23] Delamanid marketed as Deltyba is also indicated foruse as part of an appropriate combination regimen forpulmonary MDR-TB in adult patients when an effectivetreatment regimen cannot otherwise be composed forreasons of resistance or tolerability It must be administeredas directly observed therapy (DOT) because of its adverseeffect and it lasts for 24 weeks There has been no established

safe dosage for patients with renal or hepatic impairmentand children or adolescents [24]

In an effort to discover new and effective chemothera-peutic agent for the treatment of TB the antimycobacterialactivities of various phthalazin-4-yl acetamides [25] thia-zolylthiosemicarbazones [26] chromeno[32-c]pyridine-3-ylderivatives [27] [14]-thiazines [28] thieno-[23-b]thiophene[29] spirocyclohexanones derivatives [30] thieno[32-b]indoles [31] furan-2-yl derivatives [32] thiadiazoles deriv-atives [33] imidazole derivatives [34 35] acyclic deoxymon-osaccharide derivatives [36] benzoic acid hydrazine class[37] calanolideA a naturally occurring coumarin derivatives[38 39] purine derivatives [40 41] pyrrole derivatives[42 43] benzoxazine derivatives [44] diterpenoids derivedfrom plants [45 46] and quinoline and quinoxaline deriva-tives [47] have been reported

2 Synthesis of Pyrazine DerivedCarboxamides

Pyrazine carboxamide is an important component in theintensive phase of short-course treatment of TB owing to itssterilizing effect ability to act in acidic environments andexcellent synergy with rifampicin Martin et al [48] synthe-sized binuclear analogues with the ndashCONHndash bridge connect-ing the pyrazine and benzene rings with antimycobacterialactivity They proposed the formation of centrosymmetricdimer pairs with the peptidic carboxamido group of somepeptides needed for binding to the receptor site possibly byhydrogen bond formation

The target compounds were synthesized by microwaveassisted coupling reaction of methyl ester of substitutedpyrazine carboxylic acids (2) with ring substituted benzy-lamines (3) which yielded series of substituted N-benzylpyrazine-2-carboxamides (4andashj) (Scheme 1) They usedhydrophobic electron withdrawing (halogens) alkylsubstituents on the pyrazine (methyl t-butyl) and theircombination of substituents (alkyl alkoxy acetyl OH andhalogens) on benzene part

The antimycobacterial evaluation of the compoundsshowed no improvement in comparison with pyrazinamideThe most active compound in this series is compound 4c(MIC 25 120583gmL) against pyrazinamide (MIC 625 120583gmL)

Dole zal et al [49] further reported the synthesis ofnew derivatives of N-phenyl pyrazine-2-carboxamide (7andashl)with improved antimycobacterial activity They achieved thisby reacting pyrazine-2-carboxylic 6-chloropyrazine-2-car-boxylic 5-tert-butylpyrazine-2-carboxylic or 5-tert-butyl-6-chloropyrazine-2-carboxylic acid respectively (50mmol)with thionyl chloride (55mL 750mmole) in dry toluene(20mL) on reflux for 1 h They removed the excess thionylchloride by repeated evaporation with dry toluene in vacuoThe crude acyl chloride (5) dissolved in dry acetone (50mL)was added drop wise to a stirred solution of the correspond-ing substituted amine (6) (50mL) and pyridine (50mmole)in dry acetone (50mL) kept at room temperature After theaddition was completed stirring was continued for 30min

International Journal of Medicinal Chemistry 3

N

N

OH

O

MeOHN

N

OMe

O

2

3 N

N

N

OH

4

R1

R2

R1 R1

R2 R2

NH2

R3

R31

Scheme 1 Synthesis of pyrazine carboxamides

N

N

OH

O

N

N

Cl

ON

N

N

OH

1 57

6R1

R1

R2

R2

R1

R2

R3

SOCl2R3

H2N

ndashHCl

Scheme 2 Synthesis of new derivatives of pyrazine carboxamides

N

N

O

7aN

NNHNH

NH NH

O Br

7e

N

NO

I7i

N

NO

ICl 7l

CH3

CH3

CH3

CH3

CH3

CF3

H3C

Figure 1 SAR of tetrahydropyrazolopyrimidine carboxamides

and then the reaction mixture was poured into cold water(100mL) and the crude amide was collected and purified bythe column chromatography (Scheme 2)

The antimycobacterial activity screening of the twelvecompounds showed that several novel derivatives had rel-atively higher activity against M tuberculosis namely N-(4-trifluoromethyl phenyl) pyrazine-2-carboxamide N-(2-bromo-3-methylphenyl) pyrazine-2-carboxamide and N-(3-iodo-4-methylphenyl) pyrazine-2-carboxamideThese struc-tures exhibitedminimum inhibitory concentrationslt2mgLThey also carried out antimycobacterial evaluation at thetuberculosis antimicrobial acquisition and coordinatingfacility (TAACF) program 5-tert-Butyl-6-chloro-N-(3-iodo-4-methylphenyl) pyrazine-2-carboxamide was the mostactive compound at the TAACF antituberculosis screening

(IC90

= 0819 120583gmL) In the SAR the importance of iodinesubstitution in position 3 of benzene ring for the antimy-cobacterial activity was identified mostly in compounds 7iand 7l The discrepancy between the results of two antimyco-bacterial assays was explained by using different laboratoryconditions (pH growth medium) Acidic pH (pH 55) iscrucial for the mode of action of PZA where PZA as aprodrug is converted into active form of pyrazinoic acidinside the bacilli [50] Although compounds 7a 7e 7iand 7l (Figure 1) had better antitubercular activity (MICof 2 2 lt2 and 4mgL) than pyrazinamide (MIC 8mgL)in the experiment performed at the Czech Republic onlycompound 7l (IC

900819mgmL) maintained its lead against

pyrazinamide (IC90gt 20b) [51] when the experimental

conditions were changed


CHO

OH O O

NH

O

O

NHN

O R

O

NH

O N

S

O

R

8 9 10

11

12

R

CHO

13

BrCH2CO2C2H5

Dry acetone K2CO3Reflux 186 h

CO2C2H5NH2

ZnCl2 reflux 142h

DMF EtOH reflux 85h

Mercaptoacetic acid 14minus dioxan

NH2NH2middotH2O EtOH

Scheme 3 Synthesis of naphthofuran carboxamides

3 Synthesis of N-[(2I-Substituted Phenyl)-13I-thiazol-5-one]-naphtho[21-b]furan-2-carboxamide Derivatives

Murugan et al [52] reported the synthesis of N-[(2I-sub-stituted phenyl)-13I-thiazol-5-one]-naphtho[21-b]furan-2-carboxamide derivatives (12ndash15) A mixture of 2-hydroxy-1-naphthaldehyde (8) ethyl bromoacetate and anhydrouspotassium carbonate was heated under reflux for 2435 hThereaction mixture was filtered and potassium carbonate waswashedwith acetonewhichwas evaporated to get carboxylate(9) To this point hydrazine hydrate and ethanol were addedand refluxed for 183 h The excess ethanol was distilled off toget the respective carbohydrazide (10) The carbohydrazide10 was mixed with a solution of various substituted aromaticaldehydes (11) in ethanol in DMF The reaction mixture wasrefluxed for 82 h cooled to room temperature and pouredinto crushed ice to yield carboxamide (12) To the carbox-amide 12 in 14-dioxane mercaptoacetic acid and catalyticamount of anhydrous zinc chloride were added The mixturewas refluxed for 44 h cooled and poured into sodiumbicarbonate solution to remove unreacted mercaptoaceticacid which was filtered to get the final products (14ndash17)(Scheme 3)

The antitubercular activities of the compounds wereassessed againstM tuberculosis usingmicroplate AlamarBlueassay (MABA) They reported four (14ndash17) (Figure 2) of thetested compounds to be active at concentrations of 50 and100 120583gmL (Table 1)

4 Synthesis of NN-Diaryl-4-(45-dichloro-imidazole-2-yl)-14-dihydro-26-dimethyl-35-pyridine Dicarboxamides

The dihydropyridines (DHPs) are well known drugs for thetreatment of hypertension and cardiovascular disorders [53]In addition 14-DHP class of compounds is excellent synthon

Table 1 MIC of naphthofuran carboxamides

Compdnumberconc 120583gmL

100 50 25 125 625 3125 16 08 02

14 S S R R R R R R R15 S S R R R R R R R16 S S R R R R R R R17 S S R R R R R R RS = sensitive R = resistance

for the development of antitubercular agents [54ndash56] It hasbeen demonstrated previously that substitution of arylamidegroup for dicarboxylic ester moiety reduces the Ca2+ channelblocker activity and increases antitubercular activity [57]

In continuation of search for 14-DHPs with improvedantitubercular activity Gaveriya et al [58] synthesizedNN-diaryl-4-(45-dichloroimidazole-2-yl)-14-dihydro-26-dimethyl-35-pyridine dicarboxamides (20andashj) The diarylswere synthesized by condensation of 45-dichloroimidazole-2-carboxaldehyde (18) N-aryl acetoacetamide (19) andammonium acetate in methanol 45-Dichloroimidazole-2-carboxaldehyde 18 was prepared according to literature[59] and N-aryl acetoacetamides 19 according to modifiedClemens method [60] by simple condensation of 226-trimethyl-13-dioxin-4-one with appropriate aryl amine(Scheme 4)

They tested all compounds againstM tuberculosisH37Rv

strain at the concentration of 625 120583gmL using DMSOas a solubilizing agent The antitubercular activity resultindicated that the substitution of 45-dichloroimidazole ringat 4-position of 14-DHP affects the antitubercular activ-ity when 35-diester group in classic DHP structure wasreplaced by carboxamide moiety On comparison the most


O

NH NH

ON

S

O

HOO

ON

S

O

OH

O

NH

ON

S

O

O

NH

ON

S

O14 15

1617

O2N

NO2

Figure 2

NH

NOO

ClCl

R R

N NH

ClCl

CHO

O O

R1819

20

+H3C

NH4OAc MeOHReflux NH

NHNH

NH

CH3H3C

Scheme 4 Synthesis of pyridine dicarboxamides

active compound is 20d with 3-chlorophenyl group at 35-dicarboxamide position 3-Nitrophenyl and 4-nitrophenylsubstituted compounds were also relatively active but othersubstitutions did not show good activity Although none ofthe new compounds had antibacterial activity comparablewith rifampicin the results serve as valuable probes to studythe structure function relationship for antitubercular activity

5 Synthesis of Novel ThiadiazolylPyrrolidine Carboxamides

A new direction in the synthesis of antitubercular agentsis directed on the design of molecules acting as enzymeinhibitors The target enzyme should play a vital role in anyphase of the life cycle of the pathogen and should be absentin the host Enoyl-acyl carrier protein reductase is a FASII enzyme involved in the bacterial fatty acid biosyntheticpathway in the mycobacterium and other bacteria [61]These

enzymes are involved in fatty acid elongation in the cell wallsynthesis The prime TB drug isoniazid is reported to bea potent enoyl-ACP reductase inhibitor but requires initialactivation by Kat G a catalase peroxidase enzyme [62] Thisactivation step necessitated the search for new antitubercularagentswhich can act as direct enoylACP reductase inhibitorsThis prompted Boyne et al [63] to synthesize thiadiazolylpyrrolidine carboxamides (26andashe) and tested their enoylACPreductase inhibition activity

In their synthesis 5-oxo-1-phenylpyrrolidine-3-carbox-ylic acid 23was synthesized by refluxing amixture of itaconicacid [21] aniline [22] and water for 1 h or until the odourof aniline becomes faint after which the reaction was chilledfor 1 h The synthesis of 2-amino-5-(4-substituted)phenylaryl-134-thiadiazole 25 was achieved by dissolving aromaticaldehyde and thiosemicarbazide respectively in warm alco-hol and warm water and mixing the two solutions slowlywith stirring The target compounds were synthesized bydissolving compounds 23 and 25 in dry DMF HBTU and


HO

OHO

ON

O

OHO

NN

S

H NN

S

R

21 22

23

24 25

HBTUDIEA

N

NN

SN

O

H

R

O26

H2C+

NH2

NH2

NH2

45min

5h stirring

Reflux 45min

FeCl380ndash90∘C

Scheme 5 Synthesis of thiazolyl pyrrolidine carboxamides

Table 2 SAR and MIC of thiazolyl pyrrolidine carboxamides

Compd number MIC (120583gmL) R26a 25 H26b 50 Cl26c 50 CH3

26d 25 OCH3

26e 25 NO2

DIEA were added and the mixture was stirred for 5 h at23∘C The reaction was quenched using NaCl solution andthe mixture extracted with ethyl acetate The combined ethylacetate layer waswashedwith 1NHCl and thenwith saturatedsodium bicarbonate followed by brine (Scheme 5)

The antimycobacterial activities of the compounds wereassessed againstM tuberculosis using MABAThe antituber-cular activities are as presented in Table 2

6 Synthesis of Substituted N-Phenyl-6-methyl-2-oxo-4-phenyl-1234-tetrahydroPyrimidine-5-carboxamides

Within the pyrimidines 24-diaminopyrimidines have beenreported to have IC

50of 00058120583M and a safety index

gt600 [64] The most effective derivative in the chloropy-rimidine series has an MIC of 078 120583gmL [65] whilethe most successful compound from the anilinopyrimidineseries displayed an MIC of 312 120583gmL [66] Thymidinemonophosphate derivatives have been evaluated for bindingto thymidine monophosphate kinase of M tuberculosis Themost effective inhibitor of this class has a Ki of 105 120583M[67] These results prompted Vanheusden et al [68] to syn-thesize series of N-phenyl-6-methyl-2-oxo-4-phenyl-1234-tetrahydropyrimidine-5-carboxamides [31andashv 32andashg] andevaluate their antimycobacterial activity

Virsodia et al [69] carried out the synthesis of the targetcompounds utilizing various substituted acetoacetanilides(29andashn) Compounds (29andashn) were synthesized by reactingsubstituted amines and ethyl acetoacetate in toluene with acatalytic amount of NaOH or KOH (Scheme 6) The reactionmixture was heated at 120∘C for 10ndash15 h Fourteen differentacetoacetanilides were synthesized bearing various electronwithdrawing and electron donating groups like 23-diCH

3

34-diCH3 4-CH

3 H 25-diCH

3 24-diCH

3 3-Cl-4-F 4-F

4-Cl 2-F 4-OCH3 25-diCl and 3-NO

2on the phenyl ring

Acetoacetanilides thus obtained were used as 13-diketoneadducts for the multicomponent Biginelli reaction

The acetoacetanilides (29andashn) were reacted with substi-tuted aldehydes and urea in methanol using concentratedHCl in catalytic amount to obtain the title compounds (31andashv32andashg) as depicted in Scheme 6

The antitubercular activities of the compounds weretested againstM tuberculosisH

37Rv strain Percentage inhibi-

tion data of compounds (31andashv 32andashg) are reported in Table3 Compounds 31c and 32f with dimethyl phenyl and 34-dimethylcarbamoyl side chain respectively showed 65 and63 inhibitionThusmethyl group at these positions showedhigher potency But substitutions on 4-phenyl ring also alterthe activity of compound Compound 31m was having 34-dimethylphenyl carbamoyl side chain as in compound 32fbut NO

2group is at meta-position in compound 31m which

leads to a decrease in inhibition from 63 to 13 Thuscompounds with methyl substitution on phenyl carbamoylside chain with ndashOPh or ndashNO

2substitution atmeta-position

of 4-phenyl ring weremore potent than the same substitutionon para-positionThe replacement of methyl group in phenylring of phenyl carbamoyl side chain with halogens results inthe loss of antitubercular activity Compounds with halogensubstituted at different positions of phenyl ring of phenylcarbamoyl side chain do not show good potency either withmeta- or with para-substituted 4-phenyl ring of C

5side chain

withmeta-substituted 4-phenyl ring showing good potency


O

OO

O O

CHO

R

Urea HCl MeOH

O

N

O

N

H

O

R

H

27

28

30

NaOHKOH

H3C

H3C

+

R1

R1

R2

R2

R3

R3

R4

R4

R1

R2

R3

R4

NH2

CH3

CH3NH

NHReflux 5ndash10h

toluene 110∘C10ndash15h

29andashn

31andashn 32andashg

Scheme 6 Synthesis of pyrimidine carboxamides

CHO

R

30

HS OH

O

S N

OH

O

H

R

S N

N

O

H

R

EtOH DCCNH

33

+

R1R1

R2

R2

CH3CO2KH2O

NH2

34andashd 35(andashd)ndash50(andashd)

Scheme 7 Synthesis of aryl thiazolidine carboxamides

7 Synthesis of Aryl ThiazolidineCarboxamides

Sriram et al [70] synthesized 2-(substituted aryl)-N-(substi-tuted) thiazolidine-4-carboxamides 35(andashd)ndash50(andashd) Thecompounds were synthesized from 2-(substituted aryl)-N-(substituted) thiazolidine-4-carboxamides (34andashd) 2-(Substituted aryl)-N-(substituted) thiazolidine-4-carboxylicacids were synthesized as follows Potassium acetate wasadded to a solution of L-cysteine hydrochloride 33 in waterTo this homogenous mixture ethanol and appropriate alde-hyde 30 were added The reaction was stirred below 25∘C for6 h The solid that precipitated was filtered and washed withcold ethanol and dried to afford 34andashd

They synthesized the carboxamides 35(andashd)ndash50(andashd)by mixing appropriate carboxylic acid 34andashd and DCC indichloromethane and stirred them for 10min at 0∘C To thismixture appropriate primary or secondary amine was addedand stirred for 8 h The solid urea separated was filtered off

and the organic layer was washed with water and dried oversodium sulphate and distilled under reduced pressure to yieldthe desired product (Scheme 7)

The compounds were screened for their in vitro antimy-cobacterial activity against M tuberculosis (MTB) and Msmegmatis ATCC 14468 (MC2) by agar dilution method forthe determination of MIC in duplicate The result of the MICis as given in Table 4 The structural core is presented inFigure 3

As could be read from Table 4 all the compoundsprepared showed excellent in vitro activity against MTB withMICs ranging from 012 to 2094 120583M Seventeen compounds(39a 46a 47a 50a 37b 40b 41b 43b 45b 49b 50b 36d39d 45d 46d 47d and 50d) hadMIC less than 1 120583MWhencompared to isoniazid (MIC 066 120583M) thirteen compounds(39a 37b 40b 41b 43b 45b 49b 50b 36d 39d 46d 47dand 50d) were found to be more active against MTB Threecompounds (43b 47d and 50d) were found to be morepotent than rifampicin (MIC 023 120583M) Compound 43b was


Table 3 SAR and MIC of pyrimidine carboxamides

Compd number R R1 R2 R3 R4

inhibition(120583gmL)

31a 4-OCH3 CH3 H H CH3 231b 3-OPh CH3 H H CH3 2731c 3-OPh CH3 CH3 H H 6531d 2-NO2 Cl H H H 1131e 4-NO2 CH3 H H CH3 431f 4-Cl H H H H 631g 4-OH F H H H 1831h 4-NO2 Cl H H Cl 1831i 4-OH CH3 H CH3 H 1231j 4-OH H NO2 H H 231k 3-Cl H Cl F H 4831l 4-NO2 F H H H 431m 4-NO2 H CH3 CH3 H 1331n 4-NO2 CH3 H CH3 H 1231o 3-NO2 Cl H H H 2631p 3-NO2 H Cl F H 2931q 3-NO2 F H H H 2431r 3-Cl H H F H 3831s 4-NO2 H H OCH3 H 2131t 3-NO2 H H Cl H 2931u 3-NO2 H H CH3 H 2831v 3-NO2 H H F H 3032a 3-NO2 CH3 H H H 632b 4-Cl Cl H H H 2632c 4-NO2 H H Cl H 932d 3-OPh H CH3 CH3 H 3232e 4-NO2 H H H H 2532f 3-NO2 H CH3 CH3 H 6332g 4-NO2 H Cl F H 22

S

NH

OR1

R2

Arminus

Figure 3

found to be the most active compound in vitro with MIC of012120583MagainstMTB and it was 55 and 19 timesmore potentthan isoniazid and rifampicin respectively

With respect to structural antitubercular activity in thecarboxamide end they prepared various phenyl (35ndash39)pyridyl (41-42) arylpiperazine (43ndash45) and fluoroquinolone(46ndash50) side chain Among them the order of activityfrom Table 4 is fluoroquinolone gt arylpiperazine gt pyridylgt phenyl side chain Among the phenyl ring dinitro sub-stituents showed excellent activity and the order of activity

is 24-(NO2)2gt 4-Cl gt 4-CH

3gt 4-CF

3gt 6-CH

3gt H In

the case of aryl ring halogen showed good activity and theorder of activity is as follows 4-Cl gt 5-CH

3gt 4-CH

3 In the

case of aryl ring of piperazine derivatives one can see benzylgt 4-chlorophenylgt phenyl Among the fluoroquinolones theorder of activity ismoxifloxacingt gatifloxacingt ciprofloxacingt norfloxacin gt lomefloxacin

8 Synthesis of Phenothiazine DerivedThiazolidinone Carboxamides

Phenothiazine is a bioactive heterocyclic compound of phar-maceutical importance and possesses different biologicalactivities namely antibacterial [71 72] antifungal [73] anti-tubercular [74] and anti-inflammatory activities [75]

The synthesis was achieved as reported by Sharma etal [76] as follows the starting material phenothiazine 51with 1-bromo-3-chloropropane underwent a nucleophilicsubstitution reaction yielding 10-(3-chloropropyl)-10H-phe-nothiazine compound 52 Compound 52 on reaction withurea afforded N-[3-(10H-phenothiazine-10-yl)pro pyl]ureacompound 53 Compound 53 on reaction with severalselected substituted benzaldehydes underwent a condensation reaction to afford N-[3-(10H-phenothiazine-10-yl)pro-pyl]-1198731-[(substituted phenyl)-methylidene]urea compounds54andashs The reaction of thioglycolic acid with compounds54andashs in the presence of anhydrous ZnCl

2gave new hetero-

cyclic compounds N-[3-(10H-phenothiazine-10-yl)propyl]-2-(substituted phenyl)-4-oxo-3-thiazolidine carboxamidecompounds 55andashs Compounds 55andashs on treatment withvarious selected substituted benzaldehydes in the presence ofC2H5ONa underwent a Knoevenagel condensation reaction

to yield the final products N-[3-(10H-phenothiazine-10-yl)propyl]-2-(substituted phenyl)-4-oxo-5(substituted ben-zylidene)-3-thiazolidine-carboxamide compounds 56andashs(Scheme 8)

The results of the antitubercular activities are summa-rized in Table 5 All the compounds 51 52 53andashs 54andashsand 55andashs were screened for their antitubercular activityagainst M tuberculosis (H37Rv strain) The investigation ofantimicrobial data revealed that compounds 56c 56d 56e56f 56h 56i and 56j displayed high activity compounds55h 55j 56b 56g and 56q showed moderate activity andthe other compounds showed less activity compared withstandard drugs

The compounds exhibited a structure activity relationship(SAR) because the activity of compounds varies with sub-stitution The nitrogroup-containing compounds 56h 56iand 56j showed higher activity than the chloro-group-(56cand 56d) or the bromo-group-containing compounds (56eand 56f) In addition the chloro- and bromo-derivativesalso had a higher activity than the other tested compoundsBased on the SAR it could be concluded that the activity ofcompounds depended on the electron withdrawing natureof the substituent groups The sequence of the activity is thefollowing NO

2gt Cl gt Br gt OCH

3lt OH gt CH

3


Table 4 SAR and MIC of aryl thiazolidine carboxamides

Number Ar R1 R2 MTB MC2

35aN NH

H H 1100 1100

35b -do- H F 515 51935c -do- H NO2 2094 209435d -do- OCH3 OH 1891 947

36a HNminus CH3 H H 134 264


37a ClHNminus H H 981 1960


38a

F

HNminus

H3C

H H 493 1975


39aHNminus

O2N

NO2

H H 053 208


40aN

HNminus CH3 H H 2087 2087

40b -do- H H 063 24840c -do- H NO2 908 181440d -do- OCH3 OH 115 228

41a NHNminus

CH3

H H 2087 1045


42a

N

Cl

HNminus

H H 978 487



Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued

Number Ar R1 R2 MTB MC249b -do- H F 034 13549c -do- H NO2 255 51149d -do- OCH3 OH 127 510

50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123

50b -do- H F 032 12350c -do- H NO2 244 12350d -do- OCH3 OH 015 245INH 066 gt123RIFAMPICIN 023 4557

Ciprofloxacin 471 235

7

N

NN

OH

Secondary amide linker is essential

RHS

Pyrazole ring is essential

7-position

LHS

NH is essential

NH

lowast

lowast

5

lowast(5R 7S)-active enantiomer

R1

R3

R2

Figure 4

9 Synthesis of TetrahydropyrazolopyrimidineCarboxamides

To identify a new starting point in the development of newTBdrugs the Novartis internal small molecule chemical librarywas screened for activity against Mycobacterium bovis BCGas a surrogate of M tuberculosis by measuring ATP levelsusing the BacTiter-Glo assay as described in literature [77]Subsequent hit confirmation withM tuberculosis H37Rv ledto the identification of tetrahydropyrazolo[15-a]pyrimidinescaffold as one of the hit series Two other groups have alsoindependently reported this scaffold as a hit from their ownphenotypic high-throughput screening campaigns againstTB [78ndash80] Yokokawa et al [81] described the synthesis oftetrahydropyrimidine carboxamides exploring the structureactivity relationship (SAR) and structure-property relation-ship (SPR) of this class and the results of in vivo phar-macokinetics and pharmacological evaluation of selectedcompounds in mice Their initial SAR study identified thekey pharmacophore required for anti-TB activity as sum-marized in Figure 4 The NH of the tetrahydropyrimidine

ring the secondary amide linker and the pyrazole ring wereall found to be essential to retain low micromolar valuesof MIC (minimal inhibitory concentration defined as theconcentration that prevents 50 of bacterial growth at 5days postinhibitor exposure) Significant differential anti-TBactivity of the stereoisomers at the C-5 and C-7 positionswas observed and the absolute stereochemistry of the activeenantiomer was confirmed to be 5R 7S with X-ray crystalanalysis The corresponding (5S7R) isomers were proved tobe inactive (MIC gt 20120583M) This result indicates that the(5R7S) form of this scaffold may interact appropriately withsome pocket of the yet unknown biological target inside theTB bacteria Next they focused on the exploration of SARand SPR for the phenyl left-hand side (LHS) benzyl right-hand side (RHS) and trifluoromethyl at the C-7 positionto optimize the balance of potency and physicochemicalproperties

Condensation of the aminopyrazole 58 with the cor-responding diketones 57 in acetic acid yielded the pyra-zolopyrimidines 59 as single regioisomer at the 57-positionReduction of the pyrimidine ring with sodium borohydride


S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2

BrCH2CH2CH2Cl H2NCONH2

54andashs

56andashs

55andashs

Scheme 8 Synthesis of phenothiazine derived thiazolidinone carboxamides

KOH aq EtOH

Preparative chiral HPLC

59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60

∘C(i) NaBH4 EtOH rt

65 66 67 71 72 73 and 74

Scheme 9 Synthesis of tetrahydropyrazolopyrimidine carboxamides

(NaBH4) afforded only the 57-cis isomer of the tetrahy-

dropyrimidine analogue 60 The para-methoxy group of59e was cleaved by boron tribromide (BBr

3) to give the

phenol 60e Subsequently alkaline hydrolysis of the ester60 with potassium hydroxide afforded the racemic acid 61which was separated by preparative high performance liquidchromatography (HPLC) using a chiral column to provide

the desired (5R7S) form 62 Coupled with the correspondingbenzyl amines using 2-(1H-7-azabenzotriazole-1-yl)-1133-tetramethyl uranium hexafluorophosphate (HATU) as acoupling reagent produced the target compounds 65 66 6771 72 73 and 74 as shown in Scheme 9 The synthesis ofcompounds 68 69 70 and 75 is described in Scheme 10Introduction of morpholine at the para-position of LHS


Table 5 SAR and MIC of phenothiazine derived thiazolidinonecarboxamides

Compd number50 120583gLinhibition

()

25 120583gLinhibition

()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3

Rifampicin 100Isoniazid 100

phenyl was achieved by palladium catalyzed amination ofpara-bromophenyl of LHS 64 to afford compound 68 Com-pounds 69 70 and 75 were prepared by alkylation of thepara-phenol of LHS 7 with the appropriate alkylating agents

Compound 65 exhibited the best potency against MTBH37Rv in the whole cell assay (MIC 015 120583M) however it ishighly lipophilic (log119875 = 63) and shows high plasma proteinbinding (gt990) and low aqueous solubility (lt4 120583M at pH68) which are in general unfavorable drug-like propertiesTo reduce the lipophilicity of the scaffold replacement of theLHS phenyl with 2-pyridyl and 2-furyl groups led to com-pounds 66 and 67 which were tolerated and reduced log119875significantly (by 08minus19) Introduction of polar substituentsat the para-position of the LHS phenyl afforded compounds68 69 and 70 which also reduced log119875 and achievedanti-TB activity comparable with compound 65 (Table 6)Introduction of the 2- and 3-pyridyl rings on the RHSreduced log119875 without affecting the potency (compounds 71and 72) However all of these modifications had little effecton solubility and plasma protein binding Replacement ofthe core 7-trifluoromethyl substituent with difluoromethyl in66 afforded compound 73 which interestingly also increasedaqueous solubility The combination of the LHS pyridyl withRHS pyridyl generated compound 74 which led to a signif-icant decrease in log119875 (33) and thereby increased intrinsicaqueous solubility (021 gL) However this modification alsoresulted in the loss of anti-TB activity (MIC = 522120583M)Compound 75 suffered from modest anti-TB activity despiteits improved physicochemical properties Compound 65showed a potent bactericidal effect and activity in an invitromacrophage model Furthermore 65 is active across all


Table 6 SAR and MIC of tetrahydropyrazolopyrimidine carboxamides

Compounds R1 R2 R3 MIC (120583M) log119875a Solubilityb(mM pH 68)

PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892

a log119875 high throughput measured octanolwater partition coefficient bsolubility high throughput equilibrium solubility cPPB plasma protein bindingmeasured by rapid equilibrium dialysis (RED) device

MDR-TB isolates suggesting a novel mechanism of actionStudies to elucidate a mechanism of action of this series willbe discussed elsewhere [82] The in vivo pharmacokinetics(PK) of compounds 65 66 70 and 73were evaluated inmiceby oral (po) and intravenous (iv) routes at doses of 25 and5mgkg respectively All four compounds displayed low tomoderate total systemic clearance and volume of distribution

with elimination half-lives ranging from 13 to 4 h Thesecompounds showed good oral bioavailability (45minus100) andgood oral exposure in systemic circulation In addition thesecompounds exhibited no significant CYP inhibition (basedon reversible inhibition assays using midazolam for CYP3A45 bufuralol for CYP2D6 and diclofenac for CYP 2C9as markers) and induction


KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF

Morpholine Pd(OAc)2Xantphos Cs2CO3

R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt

(i) 2-Methoxybromo ethane Cs2CO3 DMF

Or (ii) octan-3-yl-4-methyl benzene sulphonate69 70 75


10 Conclusion

This work has reviewed the synthesis and antitubercularactivities of over two hundred carboxamide derivatives Inmost of the synthesis reported there was almost always acomparison between the antitubercular activities of the novelcompounds with isoniazid rifampicin or pyrazinamide Thereview reveals the following compounds as being moreactive than isoniazid rifampicin or pyrazinamide Fromthe work of Dole zal et al [49] it was shown that fromthe antitubercular activity carried out at Czech Republiccompounds 7a 7e 7i and 7l were more potent against Mtuberculosis than pyrazinamide but only 7l was found to bemore active than pyrazinamidewhen the IC

90was carried out

at TAACF USA The work of Sriram et al [70] also revealedthat compounds 39a 37b 40b 41b 43b 45b 49b 50b36d 39d 46d 47d and 50d were more active than isoniazidwhereas compounds 43b 47d and 50d were found to bemore active than rifampicin Since rifampicin (MIC 023 120583M)is more active than isoniazid (MIC 066 120583M) it can be saidcategorically that only three of the one hundred and thirty-four new derivatives of carboxamide reviewed were found tobe more active than the existing antitubercular agents Themost active compound is 43b (MIC 012120583M) Yokokawa etal [81] also revealed compound 65 with MIC 015120583M and 67with 013120583M

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

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global epidemicrdquo Medical Clinics of North America vol 77 no6 pp 1205ndash1217 1993

[3] T M Daniel ldquoThe history of tuberculosisrdquo RespiratoryMedicine vol 100 no 11 pp 1862ndash1870 2006

[4] WHO ldquoGlobal tuberculosis control surveillance planning andfinancingrdquo Tech Rep WHO 2008

[5] M A Espinal ldquoThe global situation of MDR-TBrdquo Tuberculosisvol 83 no 1ndash3 pp 44ndash51 2003

[6] K Johnsson andPG Schultz ldquoMechanistic studies of the oxida-tion of isoniazid by the catalase peroxidase fromMycobacteriumtuberculosisrdquo Journal of the American Chemical Society vol 116no 16 pp 7425ndash7426 1994

[7] A Rattan A Kalia and N Ahmad ldquoMultidrug-resistantMyco-bacterium tuberculosis molecular perspectivesrdquo Emerging Infec-tious Diseases vol 4 no 2 pp 195ndash209 1998

[8] T Bodmer K Zurcher P Imboden and A Telenti ldquoMuta-tion position and type of substitution in the 120573-subunit of


the RNA polymerase influence in-vitro activity of rifamycinsin rifampicin-resistant Mycobacterium tuberculosisrdquo Journal ofAntimicrobial Chemotherapy vol 35 no 2 pp 345ndash348 1995

[9] A C Fluit M R Visser and F-J Schmitz ldquoMolecular detectionof antimicrobial resistancerdquo Clinical Microbiology Reviews vol14 no 4 pp 836ndash871 2001

[10] A Nayyar and R Jain ldquoRecent advances in new structuralclasses of anti-tuberculosis agentsrdquo Current Medicinal Chem-istry vol 12 no 16 pp 1873ndash1886 2005

[11] B R Bloom and C J L Murray ldquoTuberculosis commentary ona reemergent killerrdquo Science vol 257 no 5073 pp 1055ndash10641992

[12] R G Ducati A Ruffino-Netto L A Basso and D S SantosldquoThe resumption of consumptionmdasha review on tuberculosisrdquoMemorias do Instituto Oswaldo Cruz vol 101 no 7 pp 697ndash7142006

[13] R Loddenkemper D Sagebiel and A Brendel ldquoStrategiesagainst multidrug-resistant tuberculosisrdquo European RespiratoryJournal Supplement vol 36 pp 66sndash77s 2002

[14] G di Perri and S Bonora ldquoWhich agents should we use for thetreatment of multidrug-resistant Mycobacterium tuberculosisrdquoJournal of Antimicrobial Chemotherapy vol 54 no 3 pp 593ndash602 2004

[15] W R Bishai and R E Chaisson ldquoShort-course chemoprophy-laxis for tuberculosisrdquo Clinics in Chest Medicine vol 18 no 1pp 115ndash122 1997

[16] P G Smith and A R Moss ldquoEpidemiology of tuberculosisrdquoin Tuberculosis Pathogenesis Protection and Control B BloomEd pp 47ndash59 ASM Press Washington DC USA 1994

[17] P C Hopewell ldquoOverview of clinical tuberculosisrdquo in Tuber-culosis Pathogenesis Protection and Control B Bloom Ed pp25ndash46 ASM Press Washington DC USA 1994

[18] D E Snider Jr M Raviglione and A Kochi ldquoGlobal burdenof tuberculosisrdquo in Tuberculosis Pathogenesis Protection andControl B Bloom Ed pp 3ndash11 ASM Press Washington DCUSA 1994

[19] I Bastian and R Colebunders ldquoTreatment and prevention ofmultidrug-resistant tuberculosisrdquoDrugs vol 58 no 4 pp 633ndash661 1999

[20] T G Benedek ldquoThe history of gold therapy for tuberculosisrdquoJournal of the History of Medicine and Allied Sciences vol 59no 1 pp 50ndash89 2004

[21] A J Lenaerts M A DeGroote and I M Orme ldquoPreclinicaltesting of new drugs for tuberculosis current challengesrdquoTrends in Microbiology vol 16 no 2 pp 48ndash54 2008

[22] European Medicines Agency and Committee for MedicinalProducts for HumanUse (CHMP) ldquoCHMP assessment reportrdquoTech Rep EMACHMP3298982013 European MedicinesAgency 2013

[23] httpwwwcdcgovtb[24] 2014 httpwwwemaeuropaeu[25] D Sriram P Yogeeswari P Senthilkumar et al ldquoSynthe-

sis and antimycobacterial evaluation of novel phthalazin-4-ylacetamides against log- and starved phase cultures researcharticlerdquo Chemical Biology and Drug Design vol 75 no 4 pp381ndash391 2010

[26] D Sriram P Yogeeswari P Senthilkumar and D Sangarajuldquo5-Nitrothiazolylthiosemicarbazones synthesis and antimy-cobacterial evaluation against tubercular and non-tubercularmycobacterial speciesrdquo Journal of Enzyme Inhibition andMedic-inal Chemistry vol 25 no 1 pp 105ndash110 2010

[27] D Sriram P Yogeeswari M Dinakaran D Banerjee P Bhatand S Gadhwal ldquoDiscovery of novel antitubercular 210-dihydro-4aH-chromeno[32-c]pyridin-3-yl derivativesrdquo Euro-pean Journal of Medicinal Chemistry vol 45 no 1 pp 120ndash1232010

[28] S Indumathi S Perumal D Banerjee P Yogeeswari andD Sriram ldquol-Proline-catalysed facile green protocol for thesynthesis and antimycobacterial evaluation of [14]-thiazinesrdquoEuropean Journal of Medicinal Chemistry vol 44 no 12 pp4978ndash4984 2009

[29] K Balamurugan S Perumal A S K Reddy P Yogeeswariand D Sriram ldquoA facile domino protocol for the regioselectivesynthesis and discovery of novel 2-amino-5-arylthieno-[23-b]thiophenes as antimycobacterial agentsrdquo Tetrahedron Lettersvol 50 no 45 pp 6191ndash6195 2009

[30] R R Kumar S Perumal S C Manju P Bhatt P Yogeeswariand D Sriram ldquoAn atom economic synthesis and antitubercu-lar evaluation of novel spiro-cyclohexanonesrdquo Bioorganic andMedicinal Chemistry Letters vol 19 no 13 pp 3461ndash3465 2009

[31] S V Karthikeyan S Perumal K A Shetty P Yogeeswari andD Sriram ldquoA microwave-assisted facile regioselective Fischerindole synthesis and antitubercular evaluation of novel 2-aryl-34-dihydro-2H-thieno[32-b]indolesrdquo Bioorganic and Medici-nal Chemistry Letters vol 19 no 11 pp 3006ndash3009 2009

[32] D Sriram P Yogeeswari P Dhakla P Senthilkumar DBanerjee and THManjashetty ldquo5-Nitrofuran-2-yl derivativessynthesis and inhibitory activities against growing and dormantmycobacterium speciesrdquo Bioorganic and Medicinal ChemistryLetters vol 19 no 4 pp 1152ndash1154 2009

[33] A R Bhat S G Gautham and K Mohan ldquoSynthesis of man-nich bases of 7-nitro-2-methyl 4(3H) quinazolinonerdquo IndianJournal of Heterocyclic Chemistry vol 9 pp 319ndash320 2000

[34] C K Stover P Warrener D R VanDevanter et al ldquoA small-molecule nitroimidazopyran drug candidate for the treatmentof tuberculosisrdquo Nature vol 405 no 6789 pp 962ndash966 2000

[35] W R Baker C Shaopei and E L Keeler ldquoBactericides treat-ing pathogenic infections of mycobacteria clostridium cryp-tosporidium or helicobacter and multidrug-resistant tubercu-losisrdquo US Patent 6087358-A 2000

[36] R Pathak C S Pant A K Shaw et al ldquoBaylis-Hillman reactionconvenient ascending syntheses and biological evaluation ofacyclic deoxy monosaccharides as potential antimycobacterialagentsrdquo Bioorganic and Medicinal Chemistry vol 10 no 10 pp3187ndash3196 2002

[37] D G Rando D N Sato L Siqueira et al ldquoPotential tuber-culostatic agents Topliss application on benzoic acid [(5-Nitro-thiophen-2-yl)-methylene]-hydrazide seriesrdquo Bioorganicamp Medicinal Chemistry vol 10 pp 557ndash560 2002

[38] T C McKee C D Covington R W Fuller et al ldquoPyra-nocoumarins from tropical species of the genus Calophylluma chemotaxonomic study of extracts in the National CancerInstitute Collectionrdquo Journal of Natural Products vol 61 no 10pp 1252ndash1256 1998

[39] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIV coum-arins from calophyllum seed oilrdquo Bioorganic and MedicinalChemistry Letters vol 8 no 24 pp 3475ndash3478 1998

[40] A K Bakkestuen L L Gundersen G Langli F Liu and JM Nolsoe ldquo9-Benzylpurines with inhibitory activity againstMycobacterium tuberculosisrdquo Bioorganic and Medicinal Chem-istry Letters vol 10 pp 1207ndash1219 2000


[41] L L Gundersen J Nissen-Meyer and B Spilsberg ldquoSynthesisand antimycobacterial activity of 6-arylpurines the require-ments for the N-9 substituent in active antimycobacterialpurinesrdquo Journal ofMedicinal Chemistry vol 45 no 6 pp 1383ndash1386 2002

[42] M Biava R Fioravanti G C Porretta D Deidda C Maulluand R Pompei ldquoNew pyrrole derivatives as antimycobacterialagents analogs of BM212rdquo Bioorganic and Medicinal ChemistryLetters vol 9 no 20 pp 2983ndash2988 1999

[43] R Ragno G R Marshall R di Santo et al ldquoAntimycobacterialpyrroles synthesis anti-Mycobacterium tuberculosis activityand QSAR studiesrdquo Bioorganic and Medicinal Chemistry vol 8no 6 pp 1423ndash1432 2000

[44] K Waisser J Gregor L Kubicova et al ldquoNew groups of anti-mycobacterial agents 6-chloro-3-phenyl-4-thioxo-2H-13-benzoxazine-2(3H)-ones and 6-chloro-3-phenyl-2H-13-benzox-azine-24(3H)-dithionesrdquo European Journal ofMedicinal Chem-istry vol 35 pp 733ndash741 2000

[45] A Ulubelen G Topcu and C B Johansson ldquoNorditerpenoidsand diterpenoids from Salvia multicaulis with antituberculousactivityrdquo Journal of Natural Products vol 60 no 12 pp 1275ndash1280 1997

[46] G A Wachter S G Franzblau G Montenegro et al ldquoA newantitubercular mulinane diterpenoid from Azorella madrepor-ica closrdquo Journal of Natural Products vol 61 no 7 pp 965ndash9681998

[47] S J Drews F Hung and Y Av-Gay ldquoA protein kinase inhibitoras an antimycobacterial agentrdquo FEMS Microbiology Letters vol205 no 2 pp 369ndash374 2001

[48] D Martin Z Jan C Carillo et al ldquoSubstituted N-benzyl-pyrazine-2-carboxamides their synthesis hydro-lipophilicproperties and evaluation of their antimycobacterial andphotosynthesis-inhibiting activityrdquo in Proceedings of the 15thInternational Conference on Synthetic Organic Chemistry 2011

[49] M Dolezal J Zitko D Kesetovicova J Kunes and M Svo-bodova ldquoSubstituted N-phenylpyrazine-2-carboxamides syn-thesis and antimycobacterial evaluationrdquoMolecules vol 14 no10 pp 4180ndash4189 2009

[50] M M Wade and Y Zhang ldquoEffects of weak acids UV andprotonmotive force inhibitors on pyrazinamide activity againstMycobacterium tuberculosisin vitrordquo Journal of AntimicrobialChemotherapy vol 58 no 5 pp 936ndash941 2006

[51] TAACF httpwwwtaacforgProcess-texthtmnhdp-text[52] V Murugan M Shukla K M Geetha A K Ashwini

and V Singh ldquoSynthesis and biological activities of N-[(21015840-Substituted phenyl)-11015840 31015840-thiazol-5-one]-naphtho[21-b]furan-2-carboxamide derivativesrdquo Der Pharma Chemica vol 3 no 4pp 509ndash516 2011

[53] C S M Lourenco V N M de Souza A C Pinheiro et alldquoEvaluation of anti-tubercular activity of nicotinic and isoniazidanaloguesrdquo Arkivoc no 15 pp 181ndash191 2007

[54] R Mannhold ldquoMedicinal chemistry of DHP-like calciumantagonistsrdquo Drugs of Today vol 30 no 2 pp 103ndash122 1994

[55] P S Eharkar B Desai H Gaveria et al ldquoThree-dimen-sional quantitative structure-activity relationship of 14-dihy-dropyridines as antitubercular agentsrdquo Journal of MedicinalChemistry vol 45 no 22 pp 4858ndash4867 2002

[56] B Desai D Sureja Y Nalapara A Shah and A K SaxenaldquoSynthesis and QSAR Studies of 4-Substituted phenyl-26-dimethyl-3 5-bis-N-(substituted phenyl)carbamoyl-14-dihydropyridines as potential antitubercular agentsrdquo Bioorganicamp Medicinal Chemistry vol 9 pp 1993ndash1998 2001

[57] H Gaveriya B Desai V Vora and A Shah ldquoSynthesis andantitubercular activity studies of some unsymmetrical 14-dihydropyridinesrdquo Indian Journal of Pharmaceutical Sciencesvol 64 pp 59ndash62 2002

[58] H Gaveriya B Desai V Vora and A Shah ldquoSynthesis of somenew unsymmetrical 14-dihydropyridine derivatives as potentantitubercular agentsrdquo Heterocyclic Communications vol 5 pp481ndash484 2001

[59] M Amini L Navidpour and A Shafiee ldquoSynthesis andantitubercular activity of newNN-diaryl-4-(45- dichloroimid-azole-2-yl)-14-dihydro-26-dimethyl-35-pyridinedicarboxam-idesrdquo Daru vol 16 no 1 pp 9ndash12 2008

[60] A Shafiee A R Dehpour F Hadizadeh and M Azimi ldquoSyn-theses and calcium channel antagonist activity of nifedipineanalogue with methylsulfonylimidazolyl substituentrdquo Pharma-ceutica Acta Helvetiae vol 73 no 2 pp 75ndash79 1998

[61] R J Clemens and J A Hyatt ldquoAcetoacetylation with 226-trimethyl-4H-13-dioxin-4-one a convenient alternative todiketenerdquo The Journal of Organic Chemistry vol 50 no 14 pp2431ndash2435 1985

[62] A Kumar and M I Siddiqi ldquoRecent progress in the develop-ment of mycobacterium tuberculosis enoyl acyl carrier proteinreductase inhibitors as antitubercular agentsrdquo Biobytes vol 42009

[63] M E Boyne T J Sullivan C W Ende et al ldquoTargeting fattyacid biosynthesis for the development of novel chemothera-peutics against Mycobacterium tuberculosis evaluation of A-ring-modified diphenyl ethers as high-affinity InhA inhibitorsrdquoAntimicrobial Agents and Chemotherapy vol 51 no 10 pp3562ndash3567 2007

[64] S George and T K Ravi ldquoDesign synthesis and antitubercularscreening of certain novel thiadiazolyl pyrrolidine carboxam-idesas enoyl acp reductase inhibitorsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 3 no 4 pp 280ndash284 2011

[65] A Rosowsky R A Forsch and S F Queener ldquoInhibition ofPneumocystis carinii Toxoplasma gondii and Mycobacteriumavium dihydrofolate reductases by 24-diamino-5-[2-methoxy-5-(120596-carboxyalkyloxy)benzyl]pyrimidines marked improve-ment in potency relative to trimethoprim and species selectivityrelative to piritreximrdquo Journal of Medicinal Chemistry vol 45no 1 pp 233ndash241 2002

[66] N Agarwal P Srivastava S K Raghuwanshi et al ldquoChloropy-rimidines as a new class of antimicrobial agentsrdquoBioorganic andMedicinal Chemistry vol 10 no 4 pp 869ndash874 2002

[67] J Morgan R Haritakul and P A Keller ldquoAnilinopyrimidinesas novel antituberculosis agentsrdquo Bioorganic and MedicinalChemistry Letters vol 13 no 10 pp 1755ndash1757 2003

[68] V Vanheusden H Munier-Lehmann M Froeyen et al ldquo31015840-C-branched-chain-substituted nucleosides and nucleotides aspotent inhibitors of Mycobacterium tuberculosis thymidinemonophosphate kinaserdquo Journal of Medicinal Chemistry vol46 no 18 pp 3811ndash3821 2003

[69] V Virsodia R R S Pissurlenkar D Manvar et al ldquoSynthe-sis screening for antitubercular activity and 3D-QSAR stud-ies of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1234-tetrahydro-pyrimidine-5-carboxamidesrdquo European Journal ofMedicinal Chemistry vol 43 no 10 pp 2103ndash2115 2008

[70] D Sriram P Yogeeswari J T Patrisha P Senthilkumar P NKurre and Y R Prasad ldquoExploring aryl thiazolidine carboxam-ides as a new class of antimycobacterialsrdquo Pharmacologyonlinevol 1 pp 185ndash195 2011


[71] T R Rawat and SD Srivastava ldquoSynthesis of new benzotriazolederivatives antimicrobial and anticonvulsant agentsrdquo IndianJournal of Chemistry B vol 38 no 5 pp 623ndash627 1999

[72] A R Trivedi A B Siddiqui and V H Shah ldquoDesign syn-thesis characterization and antitubercular activity of some 2-heterocycle-substituted phenothiazinesrdquo Arkivoc vol 2008 no2 pp 210ndash217 2008

[73] F Weng and J Tan ldquoEffects of phenothiazine drugs on serumlevels of apolipoproteins and lipoproteins in schizophrenicsubjectsrdquo Acta Pharmacologica Sinica vol 24 no 10 pp 1001ndash1005 2003

[74] A Rajasekaran and P P Tripathi ldquoSynthesis and anti-inflamma-tory activityof some 10-[(1-acyl-1H-tetrazol-5-yl)ethyl]-10H-phenothiazinesrdquo Acta Pharm Turc vol 45 pp 235ndash240 2003

[75] S Kasmi-Mir A Djafri L Paquin J Hamelin and M Rah-mouni ldquoOne-pot synthesis of 5-arylidene-2-imino-4-thiazolidi-nones undermicrowave irradiationrdquoMolecules vol 11 no 8 pp597ndash602 2006

[76] R Sharma P Samadhiya S D Srivastava and S K SrivastavaldquoSynthesis and biological activity of 4-thiazolidinone deriva-tives of phenothiazinerdquo Journal of the Serbian Chemical Societyvol 77 no 1 pp 17ndash26 2012

[77] K Pethe P C Sequeira S Agarwalla et al ldquoA chemical geneticscreen inMycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacyrdquo NatureCommunications vol 1 no 57 2010

[78] J A Maddry S Ananthan R C Goldman et al ldquoAntitubercu-losis activity of themolecular libraries screening center networklibraryrdquo Tuberculosis vol 89 no 5 pp 354ndash363 2009

[79] L Ballell R H Bates R J Young et al ldquoFueling open-sourcedrug discovery 177 small-molecule leads against tuberculosisrdquoChemMedChem vol 8 no 2 pp 313ndash321 2013

[80] E Alvarez-Ruiz L Ballell-Pages J Castro-Pichel et alldquoTetrahydropyrazolo [15-A] pyrimidine as anti-tuberculosiscompoundsrdquo Patent WO2012143522 2012

[81] F Yokokawa G Wang W L Chan et al ldquoDiscovery of tetrahy-dropyrazolopyrimidine carboxamide derivatives as potent andorally active antitubercular agentsrdquo ACS Medicinal ChemistryLetters vol 4 no 5 pp 451ndash455 2013

[82] P Bifani S Lakshminarayana S Rao et al ldquoHigh throughputidentification of a novel lethal anti-tubercular Tetrahydropy-razolopyrimidine Carboxamide and its mechanisms of inhibi-tion and resistancerdquo European Molecular Biology Organization(EMBO) In press

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


The tedious duration of therapy and resistance developedby the microorganism has made the recurrence of thedisease especially as MDR-TB and XDR-TB a globalchallenge in tuberculosis chemotherapy [11] XDR-TB isextensive or extreme drug resistance is MDR-TB that isalso resistant to three or more of the six classes of secondline drugs The increase in TB incidence during recentyears is largely due to the prevalence of TB in synergy withhuman immunodeficiency virus (HIVAIDS) epidemicwhich augments the risk of developing the disease by100-fold where 31 of new TB cases were attributed to HIVcoinfection and emergence of MDR-TB and XDR-TB strainsThe treatment of MDR-TB and XDR-TB has become a majorconcern worldwide The occurrence of TB is linked to densepopulation poor nutrition and poor sanitation Observedtreatment short-course (DOTS) strategy constitutes thecornerstone of the current protocol for the control of TB [12ndash19] Currently the recommended standard chemotherapeuticregimen for TB treatment is prescribed under DOTS Thechemotherapeutic regimen consists of an initial 2-monthphase of treatment with isoniazid (INH) rifampicin (RIF)pyrazinamide (PYR) and ethambutol (ETH) followed bya continuation phase of treatment lasting for 4 monthswith isoniazid and rifampicin Poor patience compliancecan promote the emergence of drug resistance and this isparticularly true in TB chemotherapy [20] In the last fortyyears only a few drugs have been approved by the Foodand Drug Administration (FDA) to treat TB reflectingthe inherent difficulties in discovery and clinical testing ofnew agents and lack of pharmaceutical industry researchin the area There is unequivocal need for new drugs thatshould show improvement over the existing regimens in thefollowing areas (a) shortening the total duration of effectivetreatment andor significantly reducing the total numberof doses needed to be taken under DOTS supervision(b) improving the treatment of MDR-TB which cannotbe treated with INH and RIF andor (c) providing moreeffective treatment of latentdormant TB infection whichis essential for eliminating tuberculosis [21] Recentlybedaquiline formerly known as TMC 207 was approvedby United State Food and Drug Administration for thetreatment of adult with pulmonary multidrug resistancetuberculosis when an effective treatment regimen cannototherwise be provided [22] It has no cross resistance to theavailable tuberculosis agents Bedaquiline is marketed asSIRTURO and chemically known as (1R2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthal-enyl)-1-phenyl-2-butanol Though this drug has goodantitubercular activity it needs 24 weeks of treatment therebyencouraging the development of resistance specie arisingfrom noncompliance to prescription and it has also beenshown to cause adverse effects like hemoptysis and anorexia[23] Delamanid marketed as Deltyba is also indicated foruse as part of an appropriate combination regimen forpulmonary MDR-TB in adult patients when an effectivetreatment regimen cannot otherwise be composed forreasons of resistance or tolerability It must be administeredas directly observed therapy (DOT) because of its adverseeffect and it lasts for 24 weeks There has been no established

safe dosage for patients with renal or hepatic impairmentand children or adolescents [24]

In an effort to discover new and effective chemothera-peutic agent for the treatment of TB the antimycobacterialactivities of various phthalazin-4-yl acetamides [25] thia-zolylthiosemicarbazones [26] chromeno[32-c]pyridine-3-ylderivatives [27] [14]-thiazines [28] thieno-[23-b]thiophene[29] spirocyclohexanones derivatives [30] thieno[32-b]indoles [31] furan-2-yl derivatives [32] thiadiazoles deriv-atives [33] imidazole derivatives [34 35] acyclic deoxymon-osaccharide derivatives [36] benzoic acid hydrazine class[37] calanolideA a naturally occurring coumarin derivatives[38 39] purine derivatives [40 41] pyrrole derivatives[42 43] benzoxazine derivatives [44] diterpenoids derivedfrom plants [45 46] and quinoline and quinoxaline deriva-tives [47] have been reported

2 Synthesis of Pyrazine DerivedCarboxamides

Pyrazine carboxamide is an important component in theintensive phase of short-course treatment of TB owing to itssterilizing effect ability to act in acidic environments andexcellent synergy with rifampicin Martin et al [48] synthe-sized binuclear analogues with the ndashCONHndash bridge connect-ing the pyrazine and benzene rings with antimycobacterialactivity They proposed the formation of centrosymmetricdimer pairs with the peptidic carboxamido group of somepeptides needed for binding to the receptor site possibly byhydrogen bond formation

The target compounds were synthesized by microwaveassisted coupling reaction of methyl ester of substitutedpyrazine carboxylic acids (2) with ring substituted benzy-lamines (3) which yielded series of substituted N-benzylpyrazine-2-carboxamides (4andashj) (Scheme 1) They usedhydrophobic electron withdrawing (halogens) alkylsubstituents on the pyrazine (methyl t-butyl) and theircombination of substituents (alkyl alkoxy acetyl OH andhalogens) on benzene part

The antimycobacterial evaluation of the compoundsshowed no improvement in comparison with pyrazinamideThe most active compound in this series is compound 4c(MIC 25 120583gmL) against pyrazinamide (MIC 625 120583gmL)

Dole zal et al [49] further reported the synthesis ofnew derivatives of N-phenyl pyrazine-2-carboxamide (7andashl)with improved antimycobacterial activity They achieved thisby reacting pyrazine-2-carboxylic 6-chloropyrazine-2-car-boxylic 5-tert-butylpyrazine-2-carboxylic or 5-tert-butyl-6-chloropyrazine-2-carboxylic acid respectively (50mmol)with thionyl chloride (55mL 750mmole) in dry toluene(20mL) on reflux for 1 h They removed the excess thionylchloride by repeated evaporation with dry toluene in vacuoThe crude acyl chloride (5) dissolved in dry acetone (50mL)was added drop wise to a stirred solution of the correspond-ing substituted amine (6) (50mL) and pyridine (50mmole)in dry acetone (50mL) kept at room temperature After theaddition was completed stirring was continued for 30min


N

N

OH

O

MeOHN

N

OMe

O

2

3 N

N

N

OH

4

R1

R2

R1 R1

R2 R2

NH2

R3

R31


N

N

OH

O

N

N

Cl

ON

N

N

OH

1 57

6R1

R1

R2

R2

R1

R2

R3

SOCl2R3

H2N

ndashHCl


N

N

O

7aN

NNHNH

NH NH

O Br

7e

N

NO

I7i

N

NO

ICl 7l

CH3

CH3

CH3

CH3

CH3

CF3

H3C




(IC90






CHO

OH O O

NH

O

O

NHN

O R

O

NH

O N

S

O

R

8 9 10

11

12

R

CHO

13

BrCH2CO2C2H5


CO2C2H5NH2

ZnCl2 reflux 142h

DMF EtOH reflux 85h











100 50 25 125 625 3125 16 08 02







O

NH NH

ON

S

O

HOO

ON

S

O

OH

O

NH

ON

S

O

O

NH

ON

S

O14 15

1617

O2N

NO2

Figure 2

NH

NOO

ClCl

R R

N NH

ClCl

CHO

O O

R1819

20

+H3C


NHNH

NH

CH3H3C








HO

OHO

ON

O

OHO

NN

S

H NN

S

R

21 22

23

24 25

HBTUDIEA

N

NN

SN

O

H

R

O26

H2C+

NH2

NH2

NH2

45min

5h stirring

Reflux 45min

FeCl380ndash90∘C




26d 25 OCH3

26e 25 NO2








3

34-diCH3 4-CH

3 H 25-diCH

3 24-diCH

3 3-Cl-4-F 4-F


2on the phenyl ring










5side chain



O

OO

O O

CHO

R

Urea HCl MeOH

O

N

O

N

H

O

R

H

27

28

30

NaOHKOH

H3C

H3C

+

R1

R1

R2

R2

R3

R3

R4

R4

R1

R2

R3

R4

NH2

CH3

CH3NH

NHReflux 5ndash10h


29andashn

31andashn 32andashg


CHO

R

30

HS OH

O

S N

OH

O

H

R

S N

N

O

H

R

EtOH DCCNH

33

+

R1R1

R2

R2

CH3CO2KH2O

NH2














S

NH

OR1

R2

Arminus

Figure 3




3gt 4-CF

3gt 6-CH

3gt H In


3gt 4-CH

3 In the





2gave new hetero-





2gt Cl gt Br gt OCH

3lt OH gt CH

3




35aN NH

H H 1100 1100






38a

F

HNminus

H3C

H H 493 1975


39aHNminus

O2N

NO2

H H 053 208


40aN



41a NHNminus

CH3

H H 2087 1045


42a

N

Cl

HNminus

H H 978 487



Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

N

OH

O

MeOHN

N

OMe

O

2

3 N

N

N

OH

4

R1

R2

R1 R1

R2 R2

NH2

R3

R31


N

N

OH

O

N

N

Cl

ON

N

N

OH

1 57

6R1

R1

R2

R2

R1

R2

R3

SOCl2R3

H2N

ndashHCl


N

N

O

7aN

NNHNH

NH NH

O Br

7e

N

NO

I7i

N

NO

ICl 7l

CH3

CH3

CH3

CH3

CH3

CF3

H3C




(IC90






CHO

OH O O

NH

O

O

NHN

O R

O

NH

O N

S

O

R

8 9 10

11

12

R

CHO

13

BrCH2CO2C2H5


CO2C2H5NH2

ZnCl2 reflux 142h

DMF EtOH reflux 85h











100 50 25 125 625 3125 16 08 02







O

NH NH

ON

S

O

HOO

ON

S

O

OH

O

NH

ON

S

O

O

NH

ON

S

O14 15

1617

O2N

NO2

Figure 2

NH

NOO

ClCl

R R

N NH

ClCl

CHO

O O

R1819

20

+H3C


NHNH

NH

CH3H3C








HO

OHO

ON

O

OHO

NN

S

H NN

S

R

21 22

23

24 25

HBTUDIEA

N

NN

SN

O

H

R

O26

H2C+

NH2

NH2

NH2

45min

5h stirring

Reflux 45min

FeCl380ndash90∘C




26d 25 OCH3

26e 25 NO2








3

34-diCH3 4-CH

3 H 25-diCH

3 24-diCH

3 3-Cl-4-F 4-F


2on the phenyl ring










5side chain



O

OO

O O

CHO

R

Urea HCl MeOH

O

N

O

N

H

O

R

H

27

28

30

NaOHKOH

H3C

H3C

+

R1

R1

R2

R2

R3

R3

R4

R4

R1

R2

R3

R4

NH2

CH3

CH3NH

NHReflux 5ndash10h


29andashn

31andashn 32andashg


CHO

R

30

HS OH

O

S N

OH

O

H

R

S N

N

O

H

R

EtOH DCCNH

33

+

R1R1

R2

R2

CH3CO2KH2O

NH2














S

NH

OR1

R2

Arminus

Figure 3




3gt 4-CF

3gt 6-CH

3gt H In


3gt 4-CH

3 In the





2gave new hetero-





2gt Cl gt Br gt OCH

3lt OH gt CH

3




35aN NH

H H 1100 1100






38a

F

HNminus

H3C

H H 493 1975


39aHNminus

O2N

NO2

H H 053 208


40aN



41a NHNminus

CH3

H H 2087 1045


42a

N

Cl

HNminus

H H 978 487



Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


CHO

OH O O

NH

O

O

NHN

O R

O

NH

O N

S

O

R

8 9 10

11

12

R

CHO

13

BrCH2CO2C2H5


CO2C2H5NH2

ZnCl2 reflux 142h

DMF EtOH reflux 85h











100 50 25 125 625 3125 16 08 02







O

NH NH

ON

S

O

HOO

ON

S

O

OH

O

NH

ON

S

O

O

NH

ON

S

O14 15

1617

O2N

NO2

Figure 2

NH

NOO

ClCl

R R

N NH

ClCl

CHO

O O

R1819

20

+H3C


NHNH

NH

CH3H3C








HO

OHO

ON

O

OHO

NN

S

H NN

S

R

21 22

23

24 25

HBTUDIEA

N

NN

SN

O

H

R

O26

H2C+

NH2

NH2

NH2

45min

5h stirring

Reflux 45min

FeCl380ndash90∘C




26d 25 OCH3

26e 25 NO2








3

34-diCH3 4-CH

3 H 25-diCH

3 24-diCH

3 3-Cl-4-F 4-F


2on the phenyl ring










5side chain



O

OO

O O

CHO

R

Urea HCl MeOH

O

N

O

N

H

O

R

H

27

28

30

NaOHKOH

H3C

H3C

+

R1

R1

R2

R2

R3

R3

R4

R4

R1

R2

R3

R4

NH2

CH3

CH3NH

NHReflux 5ndash10h


29andashn

31andashn 32andashg


CHO

R

30

HS OH

O

S N

OH

O

H

R

S N

N

O

H

R

EtOH DCCNH

33

+

R1R1

R2

R2

CH3CO2KH2O

NH2














S

NH

OR1

R2

Arminus

Figure 3




3gt 4-CF

3gt 6-CH

3gt H In


3gt 4-CH

3 In the





2gave new hetero-





2gt Cl gt Br gt OCH

3lt OH gt CH

3




35aN NH

H H 1100 1100






38a

F

HNminus

H3C

H H 493 1975


39aHNminus

O2N

NO2

H H 053 208


40aN



41a NHNminus

CH3

H H 2087 1045


42a

N

Cl

HNminus

H H 978 487



Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O

NH NH

ON

S

O

HOO

ON

S

O

OH

O

NH

ON

S

O

O

NH

ON

S

O14 15

1617

O2N

NO2

Figure 2

NH

NOO

ClCl

R R

N NH

ClCl

CHO

O O

R1819

20

+H3C


NHNH

NH

CH3H3C








HO

OHO

ON

O

OHO

NN

S

H NN

S

R

21 22

23

24 25

HBTUDIEA

N

NN

SN

O

H

R

O26

H2C+

NH2

NH2

NH2

45min

5h stirring

Reflux 45min

FeCl380ndash90∘C




26d 25 OCH3

26e 25 NO2








3

34-diCH3 4-CH

3 H 25-diCH

3 24-diCH

3 3-Cl-4-F 4-F


2on the phenyl ring










5side chain



O

OO

O O

CHO

R

Urea HCl MeOH

O

N

O

N

H

O

R

H

27

28

30

NaOHKOH

H3C

H3C

+

R1

R1

R2

R2

R3

R3

R4

R4

R1

R2

R3

R4

NH2

CH3

CH3NH

NHReflux 5ndash10h


29andashn

31andashn 32andashg


CHO

R

30

HS OH

O

S N

OH

O

H

R

S N

N

O

H

R

EtOH DCCNH

33

+

R1R1

R2

R2

CH3CO2KH2O

NH2














S

NH

OR1

R2

Arminus

Figure 3




3gt 4-CF

3gt 6-CH

3gt H In


3gt 4-CH

3 In the





2gave new hetero-





2gt Cl gt Br gt OCH

3lt OH gt CH

3




35aN NH

H H 1100 1100






38a

F

HNminus

H3C

H H 493 1975


39aHNminus

O2N

NO2

H H 053 208


40aN



41a NHNminus

CH3

H H 2087 1045


42a

N

Cl

HNminus

H H 978 487



Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


HO

OHO

ON

O

OHO

NN

S

H NN

S

R

21 22

23

24 25

HBTUDIEA

N

NN

SN

O

H

R

O26

H2C+

NH2

NH2

NH2

45min

5h stirring

Reflux 45min

FeCl380ndash90∘C




26d 25 OCH3

26e 25 NO2








3

34-diCH3 4-CH

3 H 25-diCH

3 24-diCH

3 3-Cl-4-F 4-F


2on the phenyl ring










5side chain



O

OO

O O

CHO

R

Urea HCl MeOH

O

N

O

N

H

O

R

H

27

28

30

NaOHKOH

H3C

H3C

+

R1

R1

R2

R2

R3

R3

R4

R4

R1

R2

R3

R4

NH2

CH3

CH3NH

NHReflux 5ndash10h


29andashn

31andashn 32andashg


CHO

R

30

HS OH

O

S N

OH

O

H

R

S N

N

O

H

R

EtOH DCCNH

33

+

R1R1

R2

R2

CH3CO2KH2O

NH2














S

NH

OR1

R2

Arminus

Figure 3




3gt 4-CF

3gt 6-CH

3gt H In


3gt 4-CH

3 In the





2gave new hetero-





2gt Cl gt Br gt OCH

3lt OH gt CH

3




35aN NH

H H 1100 1100






38a

F

HNminus

H3C

H H 493 1975


39aHNminus

O2N

NO2

H H 053 208


40aN



41a NHNminus

CH3

H H 2087 1045


42a

N

Cl

HNminus

H H 978 487



Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O

OO

O O

CHO

R

Urea HCl MeOH

O

N

O

N

H

O

R

H

27

28

30

NaOHKOH

H3C

H3C

+

R1

R1

R2

R2

R3

R3

R4

R4

R1

R2

R3

R4

NH2

CH3

CH3NH

NHReflux 5ndash10h


29andashn

31andashn 32andashg


CHO

R

30

HS OH

O

S N

OH

O

H

R

S N

N

O

H

R

EtOH DCCNH

33

+

R1R1

R2

R2

CH3CO2KH2O

NH2














S

NH

OR1

R2

Arminus

Figure 3




3gt 4-CF

3gt 6-CH

3gt H In


3gt 4-CH

3 In the





2gave new hetero-





2gt Cl gt Br gt OCH

3lt OH gt CH

3




35aN NH

H H 1100 1100






38a

F

HNminus

H3C

H H 493 1975


39aHNminus

O2N

NO2

H H 053 208


40aN



41a NHNminus

CH3

H H 2087 1045


42a

N

Cl

HNminus

H H 978 487



Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






S

NH

OR1

R2

Arminus

Figure 3




3gt 4-CF

3gt 6-CH

3gt H In


3gt 4-CH

3 In the





2gave new hetero-





2gt Cl gt Br gt OCH

3lt OH gt CH

3




35aN NH

H H 1100 1100






38a

F

HNminus

H3C

H H 493 1975


39aHNminus

O2N

NO2

H H 053 208


40aN



41a NHNminus

CH3

H H 2087 1045


42a

N

Cl

HNminus

H H 978 487



Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




35aN NH

H H 1100 1100






38a

F

HNminus

H3C

H H 493 1975


39aHNminus

O2N

NO2

H H 053 208


40aN



41a NHNminus

CH3

H H 2087 1045


42a

N

Cl

HNminus

H H 978 487



Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table 4 Continued


43aN NH

H H 424 214


44aN

O

OH

O

NN

minus

H H 1768 3536


45a N NH Cl H H 1611 806


46aNN

N

OH

OF

O

minus

H H 076 151


47aN

O

OH

O

NN

F

C2H5minus

H H 078 154


48a N

O

OH

O

NN

F

F C2H5

CH3

minus

H H 288 1156


49a N

O

OH

O

NN

F

CH3

minusOCH3

H H 275 1102


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table 4 Continued


50a N

O

OH

OF

N

Nminus

OCH3

H H 067 123



7

N

NN

OH


RHS


7-position

LHS

NH is essential

NH

lowast

lowast

5


R1

R3

R2

Figure 4






S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


S

NH

S

N

Cl

S

N

N

H

O

RCHO

S

N

NH

O

N S

R

O

S

N

NH

O

N S

O

RS

N

N

H

N

O

R

51 52 53NH2

R1

R1CHO C2H5ONa

HSCH2CO2H ZnCl2


54andashs

56andashs

55andashs


KOH aq EtOH


59 60

6162

N N

OEtO

N

N N

OEtO

NH

N N

OHO

NH

N N

OHO

NH

N N

NHO

NH

O

O

NH

NH

OEtO

5758

R1

R3

R1

R1

R1

R1

R1

R3

R3

R3

R3

R3

H2N+

HATU i-PrNEt2 DMF

R2

AcOH 110∘C60


65 66 67 71 72 73 and 74




3) to give the






()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




()


()R = R1

52 20 1353 18 1054a 22 18 C6H5

54b 32 25 4-ClC6H4

54c 34 27 3-ClC6H4

54d 35 30 2-ClC6H4

54e 40 28 4-BrC6H4

54f 50 27 3-BrC6H4

54g 52 25 2-BrC6H4

54h 65 32 4-NO2C6H4

54i 68 35 3-NO2C6H4

54j 66 38 2-NO2C6H4

54k 40 25 4-CH3OC6H4

54l 42 28 3-CH3OC6H4

54m 43 23 2-CH3OC6H4

54n 38 20 4-CH3C6H4

54o 35 24 3-CH3C6H4

54p 38 25 2-CH3C6H4

54q 50 28 4-HOCH3

54r 52 30 3-HOCH3

54s 55 32 2-HOCH3

55a 35 20 C6H5

55b 55 25 4-ClC6H4

55c 60 30 3-ClC6H4

55d 60 30 2-ClC6H4

55e 68 30 4-BrC6H4

55f 70 32 3-BrC6H4

55g 75 30 2-BrC6H4

55h 70 30 4-NO2C6H4

55i 68 35 3-NO2C6H4

55j 70 35 2-NO2C6H4

55k 50 30 4-CH3OC6H4

55l 53 32 3-CH3OC6H4

55m 50 30 2-CH3OC6H4

55n 41 29 4-CH3C6H4

55o 42 28 3-CH3C6H4

55p 45 30 2-CH3C6H4

55q 70 33 4-HOCH3

55r 70 34 3-HOCH3

55s 65 33 2-HOCH3

56a 45 22 C6H5

56b 74 32 4-ClC6H4

56c 80 36 3-ClC6H4

56d 80 32 2-ClC6H4

Table 5 Continued


()


()R = R1

56e 78 30 4-BrC6H4

56f 79 30 3-BrC6H4

56g 76 29 2-BrC6H4

56h 82 32 4-NO2C6H4

56i 83 27 3-NO2C6H4

56j 81 28 2-NO2C6H4

56k 60 28 4-CH3OC6H4

56l 63 30 3-CH3OC6H4

56m 65 31 2-CH3OC6H4

56n 45 22 4-CH3C6H4

56o 49 18 3-CH3C6H4

56p 47 20 2-CH3C6H4

56q 76 24 4-HOCH3

56r 70 27 3-HOCH3

56s 65 25 2-HOCH3







PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




PPB()c (hm)

65H3C

lowast

F

lowast

CF3 015 plusmn 004 63 lt4 gt990990

66N

H3C

lowast

F

lowast

CF3 044 plusmn 01 44 9 961958

67OH3C lowast

F

lowast

CF3 013 plusmn 006 55 lt4 gt990990

68

N

NO

lowast

F

lowast

CF3 087 plusmn 018 48 lt4 982984

69OOH3C

lowast

F

lowast

CF3 044 plusmn 004 41 6 981985

70 O

O

lowast

F

lowast

CF3 073 plusmn 01 51 9 973976

71H3C

lowast

N O

lowast

CH3CF3 047 plusmn 015 51 lt4 gt990990

72H3C

lowast

NF

lowast

CF3 083 plusmn 024 49 lt4 gt990990

73N

H3C

lowast

F

lowast

CHF2 060 plusmn 02 46 212 957948

74N

H3C

lowast

N F

lowast

CF3 522 plusmn 241 32 347 819872

75N

OOH3C

lowast

NF

lowast

CF3 37 plusmn 06 32 20 878892





KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


KOH aq EtOH


N N

OEtO

N

MeO

N N

OEtO

NH

HO

N N

OHO

NH

HO

N N

OHO

NH

HO

N N

NHO

NH

HO

59e 60e61e

62e 63

N N

NHO

NH

toluene

68

64

60∘C

R3

R3

R3 R3

R3

R3

HATU i-PrNEt2 DMF


R2

R2

(for 69 and 70)

K2CO3 DMF (for 75)

(ii) BBr CHCl3 rt

(i) NaBH4 EtOH rt




10 Conclusion


90was carried out




References































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of























































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

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