26 - 2. LITERATURE REVIEW 2.1. Benzimidazoles 2.1.1. Chemistry ...

Chapter 2 Literature Review

Ph. D. Thesis Jamia Hamdard - 26 -

2. LITERATURE REVIEW

2.1. Benzimidazoles

2.1.1. Chemistry

Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound

consists of the fusion of benzene and imidazole. The most prominent benzimidazole

compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial

ligand for cobalt in vitamin B12.1

Benzimidazole, in an extension of the well-elaborated imidazole system, has been

used as carbon skeletons for N-heterocyclic carbenes. The NHCs are usually used as

ligands for transition metal complexes. They are often prepared by deprotonating an

N, N’-disubstituted benzimidazolium salt at the 2-position with a base.2,3

NH

N

1

2

34

5

6

7

Benzimidazole is a white to slightly beige solid; melting at 172 oC, boils at 360

oC, slightly soluble in water, soluble in ethanol. It is a dicyclic compound having

imidazole ring (containing two nitrogen atoms at nonadjacent positions) fused to

benzene. Benzimidazole and its derivatives are used in organic synthesis and

vermicides or fungicides as they inhibit the action of certain microorganisms.

Examples of benzimidazole class fungicides include benomyl, carbendazim,

chlorfenazole, cypendazole, debacarb, fuberidazole, furophanate, mecarbinzid,

rabenzazole, thiabendazole, thiophanate. Benzimidazole structure is the nucleus in

some drugs such as proton pump inhibitors and anthelmintic agents.

Benzimidazole, pKa = 5.68, is less basic than imidazole, but with pKa = 12.75 is

more strongly NH-acidic4. Like imidazoles, benzimidazoles display annular

tautomerism in solution, e.g.:

NH

N

1

2

34

5

6

7

R

N

HN 1

2

34

5

6

7R

Nucleophiles react faster with benzimidazoles than with imidazoles, the attack

occurring at the 2-position. For instance, on treatment with sodium amide in xylene,

1-alkylbenzimidazoles give the corresponding 2-amino compounds.

http://en.wikipedia.org/wiki/Heterocyclic

http://en.wikipedia.org/wiki/Aromatic

http://en.wikipedia.org/wiki/Benzene

http://en.wikipedia.org/wiki/Imidazole

http://en.wikipedia.org/wiki/Cobalt

http://en.wikipedia.org/wiki/Cyanocobalamin

http://en.wikipedia.org/wiki/Benzimidazole#cite_note-0

http://en.wikipedia.org/wiki/Imidazole

http://en.wikipedia.org/wiki/N-heterocyclic_carbene

http://en.wikipedia.org/wiki/Ligand

http://en.wikipedia.org/wiki/Transition_metal_complex

http://en.wikipedia.org/wiki/Benzimidazole#cite_note-1



N

N

Me

NaNH2

N

N

Me

NH2

The halogen in 2-halobenzimidazoles can be substituted by nucleophiles, e.g.

alkoxides, thiolates or amines. However, the reactions proceed more slowly than with

2-halobenzoxazoles and 2-halobenzothiazoles.

The standard synthesis for benzimidazoles is the cyclocondensation of o-

phenylenediamine or substituted o-phenylenediamines with carboxylic acids or their

derivatives.

NH

NR2

R1

NH2

NH2

R2

+ C

HO

O

R1

o-Phenylendiamine reacts with formic acid at 100°C to give benzimidazole in a yield

of over 80%. N-monosubstituted o-phenylenediamines react with other carboxylic

acids more slowly, necessitating the addition of hydrochloric or phosphoric acid. A

mixture of trifluoromethanesulfonic acid anhydride and triphenylphosphane oxide in

dichloromethane is a very efficient dehydrating agent 5.

In light of the affinity they display towards a variety of enzymes and protein

receptors, medicinal chemists would certainly classify them as privileged ‘sub-

structures’ for drug dosing. The incorporation of the nucleus is an important synthetic

strategy in studies of antimicrobial drug discovery. In the past few decades,

benzimidazole and its derivatives have received much attention due to their

chemotherapeutic values.

2.1.2. Biological Profile

2.1.2.1. Anti-inflammatory

Synthesis and anti-inflammatory activity of phenyl benzimidazole (1) was reported by

Leonardo et al 6. Compounds 1a, 1b, 1c and 1d were screened for anti-inflammatory

activity and they showed percent inhibition (22.1%, 52.2%, 54.6% and 49.6%) at 50

mg/kg each doses. By these values the compound 1c showed maximum (54.6%)

inhibition of edema at doses of 50 mg/kg.



N

HN

H2CNRR1

(1)

R= morpholine,diphenylamine,dimethylamine,imidazole

R1= Cl

2.1.2.2. Diuretic

Synthesis of 3-(2-methyl-1,2-dihydropyrimido (1,2-c)benzimidazole-1-thionyl)-6,8-

dibromo-2-substituted-3H-quinazolin-4-one (2) was reported by Srinivasan et al7.

Compound 2a and 2b showed moderate diuretic activity.

N

N N

N

N

R2

R3

O

R1

CH3

S

(2)

R1 = CH3, Br, R2 = C6H5, H, R3 = H, Br

2.1.2.3. Antimicrobial

Synthesis of benzimidazole as 1-(substituted-methyl)-2-(substituted-phenyl)

benzimidazole (3) was reported by Leonardo et al 6. Compounds 3a, 3b and 3c were

screened for their antibacterial activity against S. aureus, B. pumillus and P.

Aeurugenosa. Compound 3a showed MIC (6.25) at 100 µM/mL and exhibited good

antibacterial activity.

Synthesis of 2,3,4,-trisubstituted-1,2-dihydropyrimido[1,2-a]benzimidazole

derivatives (4) were reported by Deshmukh et al 8. The compounds were tested for

their fungicidal activities against Aspergillus niger MTCC-2255 and Penicillium

chrysogenum-NCIM-723 using Greiseofulvin as control.

N

N

H2C

R1

(3)

NR

R= piperazine, dimethylamine, diethylamine

R1= Cl

N

N N

NH2

H

CN

R

(4)

R = -OCH3, -OH



The efficient synthesis of novel 3-chloro-1-5-(2-methyl-1H-bezimidazol-2-yl)-4-

(substituted) phenylazetidin-2-one (5) was reported by Ansari et al 9. Compounds

were screened for antimicrobial activity against B. substilis and E. coli and compound

5a, 5b and 5c shown MIC at 100 µg/mL, 100 µg/mL and 200 µg/mL doses.

(5)

N

N

CH3

H2C

N N

SN

O

Ar

Cl

Ar = 2-C6H5Cl, 2-C6H5OH

2.1.2.4. Antiviral

Synthesis of 2-(benzylthio)-5, 6-dichloro-1-(β-D-ribofuranosyl)benzimidazoles (6)

was reported by Devivar et al 10

. Compounds 6a, 6b and 6c performed antiviral

activity against HSV-1 and HCMV and compound 6c shown maximum activity at

90% inhibitory concentration (µM).

N

N

R

O

OH

HO

OH

OH

HO

R = SCH3, SO2CH3, SO2C6H5

(6)

2.1.2.5. Antitumor

Some new benzimidazole-4,7-diones substituted at 2-position (7) were synthesized

and reported by Gellis et al 11

. Among compounds 7a, 7b and 7c (10µM, 8µM and

3µM), 7c performed excellent cytotoxic activity against colon (HT29), breast (T47D)

and lung (A549) cancer cell lines and shown lowest IC50 values in µM i.e., (3µM).

(7)

N

N

CH3

R1

H2N

Br

O

O

R1 = -CH=CH2(CH3)2, -CH2-CH(CH3)2NO2



2.1.2.6. Antiprotozoal

Synthesis and anti-protozoal activity of 2-(trifluoromethyl)-1H-benzimidazole (8)

were reported by Vazquez et al 12

. A series of 2-(triflouromethyl)-1H-benzimidazole

derivatives with 5 and 6 position bio isosteric substituent (-Cl, -F, -CF3, -CN) were

prepared by using short synthetic route. Analogues were tested in vitro against the

protozoa Giardia intestinals and Trichomonas vaginalis compared with Albendazole

and Metronidazole, have IC50 < 1 µM and compound (8), was more active than

Albendazole against T. vulgaris and also showed moderate antimalarial activity

against W2 and D6 strains of Plasmodium falciparum.

N

NF3C

H

CF3

(8)

2.1.2.7. Antiulcer

Series of novel pyrimidyl-thio-methylbenzimidazole (9) pyrimidyl-sulfinyl-

methylbenzimidazole (10) were synthesized and reported by Bariwal et al 13

.

Compounds evaluated for the antiulcer activity. Compound 9 and 10 at 10 and 30

mg/kg doses reduced the ulcer formation significantly comparable to standard

(Omeprazole) and 10 (sulfinyl derivative) compound was more effective than 9 (thio

derivative).

N

N

CH3

S

N

HN

H3C

(9)

N

N

CH3

S

N

HN

H3C

(10)

O

2.1.2.8. Protein Kinase Ck2 Inhibitors

QSAR studies were carried out on 4,5,6,7 tetra-bromo benzimidazole (11) derivatives

by Tripathi et al. 14

and having the inhibitory activity data (IC50) and the values

converted in to –log IC50 (µM), compound 11a (0.797), 11b (0.177), 11c (0.607), by

these values compound 11b shown effective inhibitory concentration.



N

NBr

Br

Br

BrH

R

(11)

R = NH2, Br, NHCH3

2.1.2.9. Antioxidant

Synthesis of some 6-flouro-5-substituted benzimidazole (12) were reported by Alagoz

et al. 15

in which indole and 1,4,4,4-tetramethyl-1,2,3,4-tetrahydro naphthalene groups

were attached to the 2-position ring and tested for antioxidant activity.Compound 12e

showed strong super scavenging effect on superoxide anion at 10-3

M concentration.

NHN

N

R1

R

F

H

R = 4-CH3C5H10N, 4-CH3C5H10N, 4-C6H5C4H9N2,

4-C6H5C4H9N2, 4-C6H5C4H9N2; R1 = H, Br, OCH3

(12)

2.1.2.10. Anti-Asthmatic

Syntheses of novel and functionalized benzimidazole derivatives (13) were reported

by Kumar et al 16

. Compounds were tested against PDE-1V for potential anti-

asthmatic effect, compound 13a, 13b and 13c shown inhibitory activity (3.40%,

13.52% and 8.91%) at 1µm dose. The 13b compound showed potential anti-asthmatic

activity.

(13)

R= H, C2H5, CH2CH2CH3

N

N

R



2.1.2.11. Anti-Diabetic

A synthesis of a series of novel and functionalized benzimidazole derivatives (14) was

reported by Kumar et al 16

. Compounds shown anti-diabetic activity against DPP-IV

and PTP-IB. compound 14a and 14b shown inhibitory activity against PTP-IB (1.64

%, 2.42 %) at 30µM doses and 14c shown inhibitory activity against DPP-IV (3%) at

0.3 µM doses.

(14)

N

NS

H3C

R= H, CH2CH2CH2CH3

R

H3C

2.1.2.12. Cysticidal Activity

Synthesis of novel benzimidazole derivatives (15) were reported by Alonso et al17

.

Compounds 15a, 15b and 15c had shown their in vitro activity against Taenia

crassiceps of WFU strain (22.6%, 9.3% and 5.0%) cysts’s mortality percentage.

Among three of them compound, 15c having good mortality rate.

N

NR1

R3

R4

R2

(15)

R1 = 4-nitrobenzyl formate, 4-piperidine-carbaldehyde, -Cl

R2 = R3 = H, R4 = NHCOOCH3

2.1.2.13. 5-HT3 Receptor Antagonist

Synthesis of novel benzimidazole-2-carboxylic acid amides and esters (16) were

reported by Orjales et al. 18

with a quinolidine or a tropane moiety. It was evaluated

for in vitro affinity for the 5-HT3 receptor. Synthesized compounds 16a, 16b, 16c

having 5-HT3 receptor antagonist activity (12.7, 18.4, 24.4) with ED50 values of (10.6-

19.1) mg/kg i.v. among these compound 16a having higher affinity for 5-HT3

receptor.



N

N

COR1

R2

(16)

R1= 7-methyl-7aza-bicyclo heptan-2-amine

R2=isopropyl, benzyl

2.1.2.14. Analgesic

Syntheses of a series of N-(acridin-9-yl)-4-(benzo[d]imidazol/oxazol-2-yl)

benzamides (17) have been reported by Sondhi et al 19

. Compound containing R1 =

NO2, R2 = H, R3 = H, X = NH showed significant in vitro activity against CDK-5

(IC50 = 4.6 lM) and CDK-1(IC50 = 7.4 lM) and compound having R1 = Cl, R2 = H, R3

= H, X = NH showed moderate CDK-5 inhibitory activity (IC50 = 7.5 lM). The other

compounds showed moderate anti-inflammatory and analgesic activities.

X

NR1

R2

O

NH N

R3

R1= Cl,NO2,CH3,H; R2 = H,CH3; R3 = H,OCH3;

X= NH,O

(17)

2.1.2.15. Spasmolytic

Syntheses of 2-(aryloxyaryl)-1H-benzimidazole derivatives (18) were reported by

Vazquez et al 12

. Compounds 18a, 18b and 18c showed significant antispasmodic

effect in a concentration dependent manner, IC50 1.94 µM, 1.19 µM and 1.8 µM,

compound 18c shown potent relaxant smooth muscle activity.

N

N

H

Ar

(18)

Ar = C6H5COC2H5, 4-OH-3-OCH3C6H5,

2,3,4 -trimethoxybenzene



2.1.2.16. Hypotensive

Synthesis of 9-dialkylaminomethyl-2-oxy(dioxy)phenylimidazo[1,2-a] benzimidazole

(19) was reported by Anisimova et al 20

. Compounds 19a, 19b and 19c possessed

hypotensive activity (ED50: 2.8 mg/kg, 0.8 mg/kg, 0.13 mg/kg ) ,(LD50: 121.0 mg/kg,

182 mg/kg, 143 mg/kg) and (LD50/ED50: 43.2, 227.5, 1100), the most active

compound out of these was 19c exceeded the reference drugs (Dibazole and Apressin)

(ED50: 22.1, 4.0) with respect to both the degree of the hypotensive action (ED50) and

the conditional therapeutic index (LD50/ED50).

(19)

R= 1-4 dihydroxymethylbenzene,

1-3 dihydroxymethylbenzene,

N

NN

CH2CH2N

R

CH3CH3

2.1.2.17. Antimycobacterial

Synthesis of substituted 2-polyfluroalkyl and 2-nitrobenzyl sufanyl benzimiazole (20)

were reported by Kazimierczuk et al21

. Compounds were evaluated for their activity

against mycobacterium strains and compounds which showed appreciable

antimycobacterial activity compound 20a, 20b and 20c shown their MIC values 2

µmol L-1

, 2 µmol L-1

and 4 µmol L-1

.

(20)

N

N

SR2

H

R1

R1= Cl, Br

R2= methylnitrobenzene,C4F9

Camacho et al. 22

synthesised a series of N′-substituted-2-(5-nitrofuran or 5-

nitrothiophe-2-yl)-3H-benzo[d]-imidazole-5-carbohydrazide derivatives (21) and

investigated for their abilities to inhibit β-hematin formation, hemoglobin hydrolysis

and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Selected

analogues were screened for their antitubercular activity against sensitive MTB H37Rv



and multidrug-resistant MDR-MTB strains, and cytotoxic activity against a panel of

human tumor cell lines and two nontumorogenic cell lines.

N

HN

X NO2

HN

NH

R1

O

O

(21)

R1 = H, Ar; X = O,S

2.1.2.18. Anthelmintic

Synthesis of 2-benzimidazole carbamic acid methyl ester derivatives (22) were

reported by Solominova et al 23

. Compounds 22a and 22b shown anthelmintic activity

against Nippostrongilus, Ankilostoma and Haemonhus larvae that exceeded 65% upon

per oral administration in animals (rats, sheep, dogs) at a dose of 2.5-50 mg/kg. In

another group of animal inhibition action is below 40% upon per oral administration

in a dose of 50-100 mg/kg.

X

R2N

N

NHCOOCH3

R1

(22)

R1= C O O CH2CH2 OCH3, C O NH CH2CH2C O O C H3

R2= H, X= S

2.1.2.19. Histamine H4-Receptor Antagonist

Synthesis of 2-arylbenzimidazole derivatives (23) were reported by Dutra et al. 24

and

found to bind with high affinity to the human histamine H4 receptor. Compounds 23a,

23b and 23c shown their antihistaminic activity, among three of them 23a showed

moderate affinity for H4 receptor (Ki = 124 nM) and others (Ki = 65, 95).

N

N

O N

R1

H

(23)

R2

R

H

R = methylpiperazine, dimethylpyrrolidin-3-amine,

1-5diazocanemethylamine; R1= Cl



2.1.2.20. Prostaglandin Analogs

Syntheses of 2-(1-2-methylene-3-methylene-3-hydroxyoctyl)-N-(6-methoxy

carbonylhexyl) benzimidazole (24) derivatives were reported by Bespalov et al 25

.

Synthesized compounds 24a and 24b shown comparable results with F2α

prostaglandin preparation Enzaprost and spasmogenic action of these compounds

significantly lower (4-6 times) than Enzaprost.

2.1.2.21. Anti-Amoebic

Synthesis of pyrimido [1,6-a]benzimidazole derivatives (25) were reported by Sondhi

et al 26

. Compounds 25a and 25b were carried out in-vitro against E. histolytica and

IC50 values obtained (1.82 µM, 2.62 µM) compared with the reference drug

Metronidazole had 50% inhibitory concentration (IC50) of 1.22 µM and the best IC50

value shown by 25a compound.

(25)

R1= CH3,COOH, R2= CH3, H

R1

R2NH

N

NH

NHS

CH3

2.1.2.22. Antiarrhythmic

Syntheses of 9-dialkylaminoethyl-2-oxy (dioxy) phenylimidazo [1,2-a]benzimidazole

derivatives (26) were reported by Anisimova et al 20

. Compounds exhibited the

antiarrhythmic activity. Compound 26a, 26b and 26c were evaluated the activity in

minimum effective concentration (MIC mole/L) 2.9×10-4

m/L, 2.3×10-4

m/L, 2.1×10-4

m/L with reference to Quinidine (3.1×10-4

m/L). Hence the 26a MIC value was

close to the reference drug. Concentrations but the values showed no significant

result.

N

N N

CH2CH2R

R1

R2

(26)

R= diethylamine, ethoxyethylethanamineR1= OH, R2= H

N

N

(CH2)6CO2Me

(24)

R

O

R= cyclopropylheptan-1-ol,cyclopropylheptan-1-one



2.1.2.23. Anticonvulsant

In this synthesis of novel 1H-pyrrolo (1,2-a)benzimidazole-1-one derivative (27) were

reported by Chimrri et al 27

. Compounds 27a, 27b and 27c showed (84 %, 67% and 69

%) by maximal electroshock method, at dose level 25 mg/kg orally. The compound

27a showed maximum anticonvulsant activity.

NH

N

(27)

R2

R3

R1

O

R1= Cl, F, H, R2= C6H5,CH3, R3= H

Shukla et al. 28

synthesized a series of 1-heterocyclic amino/iminomethyl-2-

substituted benzimidazoles (28) and were screened for their neuropharmacological

and monoamine-oxidase inhibitory properties. A number of such compounds showed

CNS stimulant, anticonvulsant and mono amine oxidase inhibitory activities.

N

N O

R1

CH2NR2

R

R = H,Cl,F; R1= H,CH3,C2H5;

R2 = H, C6H5

(28)

Siddiqui et al. 29

synthesized a number of new 1-[(1-(2-substituted benzyl)-1H-

benzo[d]imidazol-2-yl) methyl]-3-arylthioureas compounds (29). All the newly

synthesized compounds were screened for their anticonvulsant activity in ip MES and

sc PTZ model and were compared with the standard drug phenytoin. Majority of the

compounds exhibited significant activity against both the animal models however

compounds 29g, 29l and 29o displayed promising activity.

N

N

CH2

CH2

R

NH-C

S

NH R1

(29)

R = H, Cl ; R1

= C6H5, 2-CH3.C6H5, 3-CH3.C6H5, 4-CH3.C6H5, 2-OCH3.C6H5,

3-OCH3.C6H5, 4-OCH3.C6H5,



In seeking broad spectrum pharmacological activities of benzimidazole derivatives, a

group of 4-thiazolidinones (30) and 1,3,4-oxadiazoles (31) containing 2-mercapto

benzimidazole moiety were synthesized by Shingalapur et al. 30

and screened for in

vivo anticonvulsant activity by Maximal Electroshock (MES) model and antidiabetic

activity using Oral Glucose Tolerance Test (OGTT). Compounds 30c, 30d, 30g and

30i exhibited potent anticonvulsant results and 31c, 31d, 31h and 31i showed

excellent antidiabetic activities and also pharmacophore derived from active

molecules suggested that presence of –OH group was a common feature in all active

compounds. In DNA cleavage studies, compound 31d cleaved DNA completely as no

trace of DNA was found. On the other hand, a sharp streak was found for compounds

30c, 31a and 31d.

NH

N

SCH2CONHN

S

O

R

(30)

NH

N

(31)

SCH2

O

NN

R1

R = C6H5, 4-C6H5Cl, 2-C6H5OH, 4-C6H5OH, 4-C6H5CH3, 4-C6H5OCH3;

R1 = C6H5, 4-C6H6Cl, 2-C6H5OH, 4-C6H5OH, 3-C6H5OH, 4-C6H5CH3, 4-C6H5OCH3



2.1.3. References

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‘Benzimidazole-2-carboxylic acid amides and esters: a new class of 5HT3

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2.2. Benzothiazoles

2.2.1. Chemistry

Benzothiazole is an organosulfur compound. It is colorless, slightly viscous liquid that

is used in industry and research. A derivative of benzothiazole is the light-emitting

component of luciferin, found in fireflies. Some dyes, such as thioflavin, and

pharmaceutical drugs, such as riluzole, have benzothiazoles as a structural motif.

Chemically benzothiazole is benzfused five membered heterocyclic system containing

S and N heteroatoms. It is colorless, slightly viscous liquid with a melting point of 2

°C, and a boiling point of 227-228 °C. The density of benzothiazole is 1.238 g/ml (25

°C). It is a heterocyclic organic compound. Benzothiazole has no household use. It is

used in industry and research.

S

N

1

2

34

5

6

7

By analogy to the synthesis of benzoxazoles, benzothiazoles are obtained by

cyclocondensation of o-aminothiophenols or their salts with carboxylic acids, their

derivatives or with aldehydes1:

S

NNH2

SH

C

HO

O

R

-2H2O

R

This reaction proceeds by way of the isolable o-(acylamino) thiophenols as

intermediates. N-Arylthioamides can be cyclized oxidatively to give benzothiazoles:

S

N

R

HN R K3 [Fe (CN)6], NaOH

S

Benzothiazole (pKa = 1.2) is a weaker base than thiazole (pKa = 2.52). Butyllithium

metallates in the 2-position and haloalkanes produce the quaternary 3 alkyl

benzothiazolium salts. Electrophilic substitutions occur only on the benzene ring. For

instance, nitration with nitrating acid at room temperature yields a mixture of 4-, 5-,

6-, and 7-nitrobenzothiazole.

http://en.wikipedia.org/wiki/Organosulfur_compound

http://en.wikipedia.org/wiki/Luciferin

http://en.wikipedia.org/wiki/Thioflavin

http://en.wikipedia.org/wiki/Riluzole



2-Alkylbenzothiazoles, like 2-alkylthiazoles, are CH-acidic. They are deprotonated by

«-butyllithium in THF at -78°C. The lithium compounds react with aldehydes or

ketones giving alcohols2, e.g.:

S

N

CH3

BuLi

S

N

CH2Li

C

H

O

Ph

H2O S

N

CH2

HO

Ph

H

Luciferin, which occurs in fireflies and glowworms, upon enzymatic oxidation causes

bioluminescence in these insects3. The herbicide Benazoline serves as an example of a

synthetic benzothiazole derivative with biological activity. Polymethine dyes derived

from benzothiazoles are employed for the spectral sensitization of photographic

emulsions.

S

N

S

NH

COOH

HO

Luciferin

S

N

HO

COOH

O

Cl

Benazoline



Amnerkar et al.4 synthesized a series of 6-substituted-2-[(1-acetyl-5-substituted)-2-

pyrazolin-3-yl] aminobenzothiazole (1) using appropriate synthetic route and

evaluated experimentally against maximal electroshock test. Selected compounds

were evaluated for neurotoxicity, hepatotoxicity and behavioral study. The most

active compound, 6-methyl-2- [(1-acetyl-5-(4-chlorophenyl))-2-pyrazolin-3-

yl]aminobenzothiazole exhibited an ED50 of 25.49 mmol/kg, TD50 of 123.87 mmol/kg

and high protective index (PI) of 4.86 compared to standard drug phenytoin.

S

N

NH

R1

N

N CH3

O

HA

HB

R2

(1)

R1 = H, Cl, NO2 ; R2 = C6H5, 4-Cl-C6H5,

4- OH-C6H5, 3-OH, 4-OMe-C6H5, C4H3O,

4-OMe-C6H5



New (2/4-substituted) benzaldehyde (2-oxobenzothiazolin-3-yl) acetohydrazones (2)

were prepared and their anticonvulsant activities were tested by Cakir et al. 5 using

pentylenetetrazole induced seizure test. Some compounds were found to be the most

promising among the others.

S

N

O

HN

ON

R

R = H, 2-Cl, 4-Cl, 2-CH3, 4-CH3, 2-OCH3, 4-OCH3, 2-OH4-OH, 2-F, 4-F, 4-OCH3, 4-Br, 4-NO2, 4-N(CH3)2

(2)

A series of N-(6-substituted-1, 3-benzothiazol-2-yl)-4[((substituted amino)

carbonothionyl) amino] benzenesulfonamides (3) and N-(4-substituted phenyl)-4-

{[substituted aminocarbonothionyl] amino} benzenesulfonamides was synthesized by

Siddiqui et al. 6 in good yield and evaluated for their possible anticonvulsant activity

and neurotoxic study. Majority of the compounds were active in MES and scPTZ

tests. All the compounds were less toxic than the standard drug phenytoin.

S

N

R

NH

SO

O

HN

HN R1

S

(3)

R = Cl, Br, NO2; R1 = alkyl, aryl

Siddiqui et al. 7 prepared a series of 1, 3-benzothiazol-2-yl semicarbazones (4) and

evaluated for their anticonvulsant, neurotoxicity and other toxicity studies. Majority

of the compounds were active in MES screen. Selected compounds were checked for

their lipophilic character.

S

NNH

R

NHN

O

C

R1

R2

(4)

R = H, Cl, Br, NO2

R1 = H, CH3, R2 = H, CH3, Cl, Br



Rana et al. 8 reported a series of 1,3-benzothiazol-2-yl benzamides (5) that were

prepared and evaluated for their anticonvulsant, neurotoxicity, CNS depressant study

and other toxicity studies. Majority of the compounds were active in MES and scPTZ

screen and showed the decrease in the immobility time. None of the compounds had

shown neurotoxicity or liver toxicity.

S

N

R

NH

NH

S

O R1

R = Br, Cl, F, NO2, CH3, OCH3

R1 = H, 2-Cl, 4-Cl, 4-OCH3

(5)

Yoggeswari et al. 9 synthesized various 6-substituted benzothiazolyl-2-

thiosemicarbazones (6, 7) for anticonvulsant activity screening in maximal

electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ)

induced seizure models in mice. 6-methyl benzothiazolyl-2-thiosemicarbazone

showed anticonvulsant activity in both mice i.p. and rat oral MES screen. 6-nitro

benzothiazolyl thiosemicarbazone derivative emerged as the most promising one with

anti-MES activity in mice i.p., rat i.p. and rat p.o. evaluations. All the compounds

exhibited lesser or no neurotoxicity compared to phenytoin. The isatinimino

derivatives had shown better activity when compared to the benzylidene or

acetophenone derivatives.

NNH

NH

N

R

S

R1

R2 N

NH

NH

NR

S

R = NO2, CH3, OCH3

R1 = H, CH3, C6H5

R2 = 2-Cl, 4-N(CH3)2, 2-OH, 4-NO2

4-NH2, 4-OH, 4-Br

NH

O

R1

R = NO2, CH3, OCH3

R1= H, Cl, Br, F

(6) (7)

A number of benzothiazole derivatives were evaluated for anticonvulsant activity and

found to possess significant activity against various types of seizures. In the search of

new anticonvulsant agents having benzothiazole nucleus, Jimonet et al. 10

synthesised



a lot of substituted 2-benzothiazolamines (8). All these compounds were found to

possess significant activity.

N

S

NH2

R

R = CH3, C2H5, n-prop,

i-prop, n-but, n-pent, t-pent,

OCHF2, OCH3, CF3, C2H5

(8)

2.2.2.2. Analgesic

A series of substituted analogues based on the novel 4H-

thieno[2’,3’:4,5]pyrimido[2,1-b]benzothiazole(9) and 4H- thieno[2’,3’:4,5]pyrimido

[2,1-b]benzoxazole(10) ring systems was synthesized by Russo et al 11

. The

compounds were obtained by reaction of 2-amino-3-carbethoxy-4,5-disubstituted

thiophenes with 2-chlorobenzothiazole and 2-chlorobenzoxazole, respectively.

Starting from 2 carbomethoxy-3-aminothiophene, 1lH-thieno[3’,2’:4,5] pyrimido[2,1-

b]- benzothiazol-1l-one and 1lH-thieno[3’,2’:4,5] pyrimido[2,1-b] benzoxazol-1l-one

were prepared in the same way. Synthesized compounds were evaluated for their

potential analgesic activity in phenylquinone-induced writhing test in mice and for

their potential antiinflammatory activity in carrageenan-induced rat-paw oedema test,

in acetic-acid peritonitis assay and in croton oil-induced mouse-ear oedema test.

9,10,11,12-Tetrahydro-12H-benzothieno[2’,3’:4,5]pyrimido[2,l-b]benzoxazol-l2-one

was the most active derivative in the series in all performed tests. It showed

remarkable analgesic and antiinflammatory activities associated with an excellent

gastric tolerance.

SN

N

S

O

R1

R

S

N

N

S

O

R

R1(9)

(10)

R = H, CH3, -(CH2)4-; R1= H, CH3, -(CH2)4-, C6H5, COOC2H5

A benzothiazole-derived compound (11a) designed to mimic the Ca–Cb bond vectors

and terminal functionalities of Lys2, Tyr13 and Arg17 in x-conotoxin GVIA was

synthesized by Baell et al. 12

, together with analogues (11b–d), which had each side-



chain mimic systematically truncated or eliminated. The affinity of these compounds

for rat brain N-type and P/Q-type voltage gated calcium channels (VGCCs) was

determined. In terms of N-type channel affinity and selectivity, two of these

compounds (11a and 11d) were found to be highly promising, first generation

mimetics of x-conotoxin. The fully functionalised mimetic (11a) showed low Lm

binding affinity to N-type VGCCs (IC50 ¼1.9 lM) and greater than 20-fold selectivity

for this channel sub-type over P/Q-type VGCCs, whereas the mimetic in which the

guanidine-type side chain was truncated back to an amine (4d, IC50 ¼ 4.1 lM)

showed a greater than 25-fold selectivity for the N-type channel.

O

N

S

N

OR2

O

R3

R1

O

a = R1 = OH; R2 = (CH2)3 NH2; R3 = N=C(NH2)2

b = R1 = H; R2 = (CH2)3 NH2, R3 = N=C(NH2)2

c = R1 = OH; R2 = CH3 , R3 = N=C(NH2)2

d = R1 = OH; R2 = (CH2)3 NH2, R3 =NH2

(11)

2.2.2.3. Anticancer

A series of benzothiazole and benzoxazole linked pyrrolobenzodiazepine conjugates

(12) attached through different alkane or alkylamide spacer was prepared by Kamal et

al. 13

Their anticancer activity, DNA thermal denaturation studies, restriction

endonuclease digestion assay and flow cytometric analysis in human melanoma cell

line (A375) were investigated. One of the compounds of the series 12d showed

significant anticancer activity with promising DNA-binding ability and apoptosis

caused G0/G1 phase arrest at sub-micromolar concentrations. To ascertain the binding

mode and understand the structural requirement of DNA binding interaction,

molecular docking studies using GOLD program and more rigorous 2 ns molecular

dynamic simulations using Molecular Mechanics-Poisson–Boltzman Surface Area

(MM-PBSA) approach including the explicit solvent were carried out. Further, the

compound 12d was evaluated for in vivo efficacy studies in human colon cancer

HT29 xenograft mice.



S

N

R

O O

N

N

H

O

n

(12)

a: n = 4, R = H

b: n = 4, R = CH3

c: n = 5, R= H

d: n = 5, R= OCH3

Havrylyuk et al. 14

performed antitumor screening of several novel 4-thiazolidinones

with benzothiazole moiety. Reactions of (benzothiazole-2-yl) hydrazine with

trithiocarbonyl diglycolic acid or 6-methyl-2-aminobenzothiazole with 2-

carbethoxymethylthio-2-thiazoline-4-one have yielded starting 3- or 2-substituted 4-

thiazolidinones which have been subsequently utilized in a Knoevenagel condensation

for obtaining a series of 5-arylidene derivatives. The structures of compounds have

been determined by 1H,

13C NMR, IR and X-ray analysis. In vitro anticancer activity

of the synthesized compounds was tested by the National Cancer Institute and two of

them have revealed the anticancer activity on leukemia, melanoma, lung, colon, CNS,

ovarian, renal, prostate and breast cancers cell lines. Among tested compounds, 2-{2-

[3-(benzothiazol-2-ylamino)-4-oxo-2-thioxothiazolidin-5-ylidenemethyl]-4

chlorophenoxy}-N-(4-methoxyphenyl)-acetamide (13) was found to be the most

active candidate with average logGI50 and logTGI values −5.38 and −4.45

respectively.

HNO

O

H3COS

N

HN

S

N

Cl

O

S

(13)

Wang et al. 15

synthesised a series of novel benzothiazole-2-thiol derivatives (14) for

their anti proliferative activities on HepG2 and MCF-7 cells. Most compounds had

inhibitory effects on cell growth, and some of them were more effective than

cisplatin. Compounds 14m and 14t displayed good inhibitory activities against a panel

of different types of human cancer cell lines, with IC50 values in the low micromolar



range. Further biological evaluation indicated that 6m induced apoptosis in HepG2

cancer cells. Structure–activity relationships were also proposed.

S

N

SNH

R1

OHN

R2

O

(14)

R1

= H, Phenyl, 4-Chlorophenyl, 4-Methoxyphenyl;

R2 = Phenyl, 4-Chlorophenyl, 4-Methoxyphenyl, Methyl,

Chloromethyl

Saeed et al. 16

synthesized five series of thiourea derivatives bearing benzothiazole

moiety (15) using tetrabutyl ammonium bromide (TBAB) as phase transfer catalyst

and evaluated for anticancer activity. In preliminary MTT cytotoxicity studies, the

thiourea derivatives were found to be most potent. In MCF-7 and HeLa cells, the IC50

values were observed in the range of 18–26 μM and 38–46 μM, respectively.

S

NNH

NH

R1O

O

R

R = H, NO2, NH2, BrR1 = 4-NO2C6H4, 2-thiophene, phenyl, n-butyl

(15)

2.2.2.4. Antiviral

The identification of a novel hit compound (16) as integrase binding inhibitor has

been accomplished by means of virtual screening techniques by Mugnaini et al. 17

A

small family of structurally related molecules has been synthesized and biologically

evaluated with one of the compounds showing an IC50 = 12 lM.

R1

= 3-COOH, 2-Cl, 5-NO2, 3-OH, 4-COOH, 2-CH3, 4-Cl;

R2 = CN, H, CONH2, CH3; R

3 = H, CH3 ; X = C, N

S

NO

XR

3

R2

R1

(16)



The replacement of t-butylurea moiety by benzothiazole sulfonamide was showed by

Nagarajan et al. 18

provided protease inhibitors with improved potency and antiviral

activity since the inhibitors incorporated a variety of isosteres including the

hydroxyethylurea (17) at the protease cleavage site. Some of the compounds had

shown good oral bioavailability and half-life in rats. The synthesis of benzothiazole

derivatives led them to explore other heterocycles. During the course of their studies,

they also developed an efficient synthesis of benzothiazole-6-sulfonic acid via a two-

step procedure starting from sulfanilamide.

N

SSN

CH3

O O

NH

R

OPh

OH

(17)

R = Ph, CH3

Vicini et al. 19

synthesized a series of benzothiazole (18) and tested in vitro with the

aim of identifying novel lead compounds active against emergent and re-emergent

human and cattle infectious diseases (AIDS, hepatitis B and C, tuberculosis, bovine

viral diarrhoea). In particular, these compounds were evaluated in vitro against

representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV

(Hepadnavirus) and the single-stranded RNA+ viruses Yellow fever virus (YFV) and

Bovine viral diarrhoea virus (BVDV), both belonging to Flaviviridae. Title

compounds were also tested against representatives of Gram-positive and Gram-

negative bacteria (Staphylococcus aureus, Salmonella spp.), various atypic

mycobacterial strains (Mycobacterium fortuitum and Mycobacterium smegmatis),

yeast (Candida albicans) and mould (Aspergillus fumigatus). The benzothiazole

compounds showed a marked cytotoxicity (CC50=4–9 mM) against the human CD4+

lymphocytes (MT-4) that were used to support HIV-1 growth. For this reason, the

most cytotoxic compounds of this series were evaluated for their antiproliferative

activity against a panel of human cell lines derived from haematological and solid

tumors.



R = H, F,OC2H5; R

1 = C6H5, 2-ClC6H4, 2-NO2C6H4,

3-NO2C6H4, 3-ClC6H4, 4-NO2C6H4

S

N

N

(18)

CHR1

R


As benzothiazole has proven to be good antimicrobial agent, a novel series of Schiff

bases of benzothiazole derivatives were synthesized by Soni et al 20

. Thus

condensation of 5-[2-(1,3-benzothiazol-2-yl-amino) ethyl]-4-amino-3-mercapto-(4H)-

1,2,4-triazole 5 with appropriate aromatic aldehydes afforded 5-[2-(1,3- benzothiazol-

2-yl-amino)ethyl]-4-(arylideneamino)-3-mercapto-(4H)-1,2,4-triazoles (19).

Structures of the synthesized compounds were elucidated on the basis of elemental

analyses and spectral data. All the synthesized compounds were screened for their

antimicrobial activity.

S

N

NHCH2CH2

N

NN

N CH

SH

R

R = H, 4-OH, 2-NO2, 3-NO2, 2-Cl, 4-N(CH3)2,

3,4-OCH3

(19)

Bondock et al. 21

used enaminonitrile as key intermediate for the synthesis of

polyfunctionally substituted heterocycles (e.g. pyrazoles, isoxazole, pyrimidines,

thiazolo[3,2-a]pyrimidine, tetrazolo[1,5-a]pyrimidine, pyrido[1,2-a]pyrimidine, 1,5-

benzodiazepine, and pyrazolo[1,5-a]pyrimidine) incorporating benzothiazole moiety

(20) via its reactions with some N-nucleophiles. The newly synthesized compounds

were characterized by IR, 1H NMR and mass spectral studies. Representative

compounds of the synthesized products were tested and evaluated as antimicrobial

agents.

S

NNH N

NN N CH3

H3C

O

H2N

(20)



Patel et al. 22

prepared a novel series of schiff bases (21) and 4-thiazolidinones (22)

from the building blocks 2-chloro pyridine-3-carboxylic acid and 2-amino-6-

methoxy-benzothiazole. All of the synthesized compounds have been confirmed by

elemental analyses, IR, 1H NMR and

13C NMR spectral data. These newly

synthesized compounds were screened for their antimicrobial activity. Variable and

modest activity was observed against the investigated strains of bacteria and fungi,

however, compound 22h revealed significant antibacterial activity against Escherichia

coli. Compounds 21c, 21g and 21h, on the other hand, revealed potent antifungal

activity against Candida albicans compared to the reference drug greseofulvin.

N

CHONH

CH R

NH

S

N

OCH3

(21)

N

CONHN

NH

S

N

OCH3

S

O

R

(22)

R = H, 4-OH, 2-Cl , 2-NO2, 4-OCH3, 4-Cl, 3-OCH3-4-OH,

3-OCH3-4-OH-5-NO2, 4-NO2C4H3O (Furyl)

Desroy et al. 23

synthesized some newer benzothiazole incorporated oxazolyl pyrazole

derivatives (23) as inhibitors of bacterial heptose synthesis. HldE being a bifunctional

enzyme involved in the synthesis of bacterial heptoses was inhibited by the

synthesized compounds. They developed a biochemical assay suitable for high-

throughput screening that allowed the discovery of inhibitors of HldE kinase. Study of

the structure–activity relationship of this series of inhibitors led to highly potent

compounds.

N

S

N

OH

OON

O

CH3

NHN

(23)



Oren et al. 24

synthesised a series of multisubstituted benzoxazoles, benzimidazoles,

and benzothiazoles (24) as non-nucleoside fused isosteric heterocyclic compounds

was synthesized and tested for their antibacterial activities against various Gram-

positive and Gram-negative bacteria and antifungal activity against the fungus

Candida albicans. Microbiological results indicated that the synthesized compounds

possessed a broad spectrum of activity against the tested microorganisms at MIC

values between 100 and 3.12 μg/ml. Structure–activity relationships (SAR) studies

revealed that benzothiazole ring system enhanced the antimicrobial activity against

Staphylococcus aureus. In these sets of non-nucleoside fused heterocyclic compounds

electron withdrawing groups at position 5 of the benzazoles increased the activity

against C. albicans.

R = H,Cl; R1

= H, Cl, NO2, COOCH3; R2= H, NO2 ; Z = S,

O, NHO, NHS, NHNHH

N

S

CH2 Z R

R2

R1

(24)

Novel FabK inhibitors with antibacterial activity against Streptococcus pneumoniae

were synthesized and evaluated by Kitagawa et al 25

. Through SAR studies of our

initial hit compound 2-(1H-benz[d]imidazol-2-ylthio)-N-(6-

methoxycarbonylbenzo[d]thiazol-2-yl)acetamide, a series of novel phenylimidazole

(25) derivatives were discovered as potent FabK inhibitors.

N

SHN

HN

ON

NH

SO2Me(25)

Zitouni et al. 26

synthesised some 2-[(benzazole-2-yl) thioacetylamino] thiazole

derivatives (26) by reacting 4-methyl-2-(chloroacetylamino) thiazole derivatives with

benzazol-2-thiole in acetone in the presence of K2CO3. The chemical structures of the

compounds were elucidated by 1H NMR and FAB+-MS spectral data. The prepared

compounds were tested for antimicrobial activity and toxicity.



S

NH3C

R

NHCOCH2S

S

N R1

(26)

R = H, CH3, COOC2H5 ; R1 = H, Cl, NO2, CH3

2.2.2.6. Antimycobacterial

Patel et al. 27

condensed 2-(3-pyridyl)-5-(4- methylphenyl)-1, 3, 4-oxadiazole with

various substituted 2-hydrazino benzothiazole results in 3-(3-pyridyl)-5-(4-

methylphenyl)-4-(N-substituted-1,3-benzothiazol-2-amino)-4H-1,2,4-triazole (27)

analogs. All the compounds have been characterized by elemental analysis, IR, 1H

NMR, 13

C NMR and mass spectral data. In vitro antitubercular activity was carried

out against Mycobacterium tuberculosis H37Rv strain using Lowenstein-Jensen

medium and antimicrobial activity against various bacteria and fungi using broth

microdilution method. Compounds with substituents 6-F, 6-Br, 6-NO2, 6-CH3, 4-CH3,

4-NO2, 5-Cl, and 6-Cl emerged as promising antimicrobials. It was also observed that

the promising antimicrobials have proved to be better antituberculars. Compound with

substituent 4-Cl showed better antitubercular activity compared torifampicin.

N

N

NN

CH3NH

N S

R

(27)

R = 6-F, 6-Br, 6-NO2, 6-CH3, 4-CH3,

4-NO2, 4-Cl, 5-Cl, 6-Cl

Novel 3-nitro-2-(sub)-5,12-dihydro-5-oxobenzothiazolo[3,2-a]-1,8-naphthyridine-6-

carboxylic acids (28) have been reported by Dinakaran et al. 28

from 2,6-

dimethoxynicotinic acid and 2-aminothiophenol and evaluated for their antitubercular

activity in vitro and in vivo against Mycobacterium tuberculosis H37 Rv (MTB) and

multi-drug resistant M. tuberculosis (MDR-TB). Among the synthesized compounds,

2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-

a]-1,8-naphthyridine-6-carboxylic acid was found to be the most active compound in

vitro with MIC of 0.19 and 0.04 μM against MTB and MTR-TB, respectively. One of



the compounds showed promising activity against MDR-TB and was 208 and 1137

times more potent than gatifloxacin and isoniazid, respectively. In the in vivo animal

model it decreased the mycobacterial load in lung and spleen tissues with 2.81 and

4.94-log10 protections, respectively, at a dose of 50 mg/kg body weight.

N

N

S

O

HO O

R

N+O

O-

(28)

R = H, halo, alkyl



2.2.3. References:

1. SPG. Costa; AMFO Campos; JA Ferreira; G Kirsch. ‘New Fluorescent 1,3-

Benzothiazoles by the Reaction ofHeterocyclic Aldehydes withortho-

Aminobenzenethiol’, J. Chem. Res. (S), 1997, 314-315.

2. MV Costa; A Brembilla; D Roizard; PL Chon. ‘Action of (2-benzothiazolyl)

methyllithium with organic polar functions’, J. Heterocycl. Chem., 1991, 28,

1933-1936.

3. Y Toya; M Takagi; T Kondo; H Nakata; M Isobe; T Goto. ‘Improved

Synthetic Methods of Firefly Luciferin Derivatives for Use in Bioluminescent

Analysis of Hydrolytic Enzymes; Carboxylic Esterase and Alkaline

Phosphatase’, Bull. Chem. Soc. Jpn., 1992, 65, 2604-2610.

4. DN Amnerkar; KP Bhusari. ‘Synthesis, anticonvulsant activity and 3D-QSAR

study of someprop-2-eneamido and 1-acetyl-pyrazolin derivatives of

aminobenzothiazole’, Eur. J. Med. Chem., 2010, 45, 149–159.

5. B Cakir; E Yildirim; T Ercanli; K Erol; MF Sahin. ‘Synthesis and

anticonvulsant activity of some (2:4-substituted) benzaldehyde (2-

oxobenzothiazolin-3-yl) acetohydrazones’, Farmaco, 1999, 54, 842–845.

6. N Siddiqui; SN Pandeya; SA Khan; J Stables ; A Rana; M Alam ; MF

Arshad ; MA Bhat. ‘Synthesis and anticonvulsant activity of sulfonamide

derivatives-hydrophobic domain’, Bioorg. Med. Chem. Lett., 2007, 17, 255-

259.

7. N Siddiqui; A Rana; SA Khan; MA Bhat; SE Haque. ‘Synthesis of

benzothiazole semicarbazones as novel anticonvulsants—The role of

hydrophobic domain’, Bioorg. Med. Chem. Lett., 2007, 17, 4178-4182.

8. A Rana; N Siddiqui ; SA Khan ; SE Haque; MA Bhat. ‘N-{[(6-Substituted-

1,3-benzothiazole-2-yl)amino]carbonothioyl}-2/4-substituted benzamides:

Synthesis and pharmacological evaluation‘, Eur. J. Med. Chem., 2008,

43,1114-1122.

9. P Yogeeswari; D Sriram; S Mehta; D Nigam; MM Kumar; S Murugesan; JP

Stables. ‘Anticonvulsant and neurotoxicity evaluation of some 6-substituted

benzothiazolyl-2-thiosemicarbazones’, Farmaco, 2005, 60, 1–5.

10. P Jimonet; A Francois; M Barreau; JC Blanchard; A Boirean. Ind. J Med.

Chem., 1991, 42, 2828.



11. F Russol; G Romeol; NA Santagatil; A Caruso; V Cutuli; D Amore.

‘Synthesis of new thienopyrimidobenzothiazoles and thienopyrimido benzo

xazoles with analgesic and antiinflammatory properties’, Eur. J. Med. Chem.,

1994, 29, 569-578.

12. JB Baell; PJ Duggan; SA Forsyth; RJ Lewis; YP Lokc; CI Schroederd.

‘Synthesis and biological evaluation of nonpeptide mimetics of x-conotoxin

GVIA’, Bioorg. Med. Chem., 2004, 12, 4025–4037.

13. A Kamal; K S Reddy; M Naseer; A Khan; VCRNC Rajesh; M Shetti; J

Ramaiah; SNCVL Pushpavalli; C Srinivas; M P Bhadra; M Chourasia; G N

Sastry; A Juvekar; S Zingde; M Barkume. ‘Synthesis, DNA-binding ability

and anticancer activity of benzothiazole/benzoxazole–pyrrolo[2,1-

c][1,4]benzodiazepine conjugates’ , Bioorg. Med. Chem., 2010, 18(13), 4747-

4761.

14. D Havrylyuk; L Mosula; B Zimenkovsky; O Vasylenko; A Gzella; R Lesyk.

‘Synthesis and anticancer activity evaluation of 4-thiazolidinones containing

benzothiazole moiety’, Eur. J. Med. Chem., 2010, 11 (45), 5012-5021.

15. Z Wang; XH Shi; J Wang; T Zhou; YZ Xu; TT Huang; YF Li; YL Zhao; L

Yang; SY Yang; LT Yu; YQ Wei. ‘Synthesis, structure–activity relationships

and preliminary antitumor evaluation of benzothiazole-2-thiol derivatives as

novel apoptosis inducers’, Bioorg. Med. Chem. Lett., 2011, 21, 1097–1101.

16. S Saeed; N Rashid; PG Jones; M Ali; R Hussain. ‘Synthesis, characterization

and biological evaluation of some thiourea derivatives bearing benzothiazole

moiety as potential antimicrobial and anticancer agents’, Eur. J. Med. Chem.,

2010, 45(4), 1323-1331.

17. C Mugnaini; S Rajamaki; C Tintori; F Corelli; S Massa; M Witvrouw; Z

Debyser; V Veljkovic; M Bottaa. ‘Toward novel HIV-1 integrase binding

inhibitors: Molecular modeling, synthesis, and biological studies’, Bioorg.

Med. Chem. Lett., 2007, 17, 5370–5373.

18. SR Nagarajan; GAD Crescenzo; DP; Getman; HF Lu; JA Sikorski; JL Walker;

JJ McDonald; KA Houseman; GP Kocan; N Kishore; PP Mehta; CL Funkes-

Shippy; L Blystone. ‘Discovery of novel benzothiazolesulfonamides as potent

inhibitors of HIV-1 protease’, Bioorg. Med. Chem., 2003, 11, 4769-4777.

19. P Vicini; A Geronikaki; M Incerti; B Busonera; G Poni; CA Cabrasc; PL

Collac. ‘Synthesis and Biological Evaluation of Benzo[d]isothiazole,

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TF8-501FPH0-5&_user=9419574&_coverDate=07%2F01%2F2010&_alid=1651383861&_rdoc=1&_fmt=high&_orig=search&_origin=search&_zone=rslt_list_item&_cdi=5220&_sort=r&_st=13&_docanchor=&view=c&_ct=274&_acct=C000066168&_version=1&_urlVersion=0&_userid=9419574&md5=50ca4b953a16e5d58b20514885b20d41&searchtype=a





Benzothiazole and Thiazole Schiff Bases’. Bioorg. Med. Chem., 2003, 11,

4785–4789.

20. B Soni; MS Ranawat; R Sharma; A Bhandari; S Sharma. ‘Synthesis and

evaluation of some new benzothiazole derivatives as potential antimicrobial

agents’. Eur. J. Med. Chem., 2010, 45, 2938-2942.

21. S Bondock; W Fadaly; MA Metwally. ‘Enaminonitrile in heterocyclic

synthesis: Synthesis and antimicrobial evaluation of some new pyrazole,

isoxazole and pyrimidine derivatives incorporating a benzothiazole moiety’,

Eur. J. Med. Chem., 2009, 44, 4813-4818.

22. NB Patel; FM Shaikh. ‘Synthesis and antimicrobial activity of new 4-

thiazolidinone derivatives containing 2-amino-6-methoxybenzothiazole’,

Saudi. Pharm. J., 2010, 18, 129–136.

23. N Desroy; F Moreau; S Briet; GL Fralliec; S Floquet; L Durant; V

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activities of novel benzothiazolo naphthyridone carboxylic acid derivatives

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Pharmacother. 2009, 63, 11-18.



2.3. Isatins

2.3.1. Chemistry

Isatin or 1H-indole-2,3-dione is an indole derivative. The compound was first

obtained by Erdman and Laurent in 1841 as a product from the oxidation of indigo

dye by nitric acid and chromic acids. The compound is found in many plants. Schiff

bases of isatin are investigated for their pharmaceutical properties. It was observed

that isatin forms a blue dye if it is mixed with sulfuric acid and crude benzene. The

formation of the blue indophenin was long believed to be a reaction with benzene.

Victor Meyer was able to isolate the substance responsible for this reaction from

benzene. This new heterocyclic compound was thiophene.

NH

O

O

1

2

34

5

6

7

Isatin, an indole derivative, is a yellow to red needle crystalline solid; soluble in hot

water; melting point 198-204 0C. It is a hetero bicyclic aromatic compound with

diketone at 2 and 3 positions. Isatin class compounds are mainly used as raw material

in dye manufacturing (artificial indigo, disperse dye yellows). It has lactam (a cyclic

amide) structure which is an important part of antibiotics, such as penicillin. Cyclic

ester structures are active nucleuses in pharmacological activity and flavorings. They

are used as intermediates for the synthesis of pharmaceuticals, herbicides, and other

chemical compounds.

Isatin is commercially available. It may be prepared from cyclicizing the condensation

product of chloral hydrate, aniline and hydroxylamine in sulfuric acid. This reaction is

called the Sandmeyer isonitrosoacetanilide Isatin Synthesis and discovered by

Traugott Sandmeyer in 1919.

NH

O

O

NH2

Cl3C

OH

OH

NH2HO

NH

N

OH

O H2SO4

http://en.wikipedia.org/wiki/Indole

http://en.wikipedia.org/wiki/Auguste_Laurent

http://en.wikipedia.org/wiki/Oxidation

http://en.wikipedia.org/wiki/Indigo_dye



http://en.wikipedia.org/wiki/Nitric_acid

http://en.wikipedia.org/wiki/Chromic_acid

http://en.wikipedia.org/wiki/Schiff_base



http://en.wikipedia.org/wiki/Sulfuric_acid

http://en.wikipedia.org/wiki/Benzene

http://en.wikipedia.org/w/index.php?title=Indophenin&action=edit&redlink=1

http://en.wikipedia.org/wiki/Victor_Meyer

http://en.wikipedia.org/wiki/Chloral_hydrate

http://en.wikipedia.org/wiki/Aniline

http://en.wikipedia.org/wiki/Hydroxylamine

http://en.wikipedia.org/wiki/Sulfuric_acid

http://en.wikipedia.org/wiki/Traugott_Sandmeyer





Synthesis of 2-[1-(5,8-dihydro qinoxalino[2,3-b] indolo acetyl)-3(1-benzofuran-2-yl)-

4,5-dihydro-1H-pyrazol-5-yl]phenyl derivatives (1) were reported by Manna et al 1.

The synthesized compounds 1a, 1b, 1c showed good antimicrobial activity and MIC

were found below 10 µg/mL against E. coli (10.0, 5.0, and 8.0), P. aereuginosa (5.0,

10.0, and 9.5) and S. aureus (7.5, 8.5 and 2.5).

N

N N

N

N

O

OR

R= NO2 , OCH3, H

(1)

Synthesis of some new triazine derivatives (2) were reported by Pandeya et al 2. All

the synthesized compounds 2a-f were tested for their antimicrobial activity against 20

strains of gram negative and gram positive bacteria. Among the compounds tested, the

compound 2d and 2e showed good antimicrobial activity in comparison to the

standard Suphamethoxazole. Compound 2e was found to be most active in series

against H. Pyloria with MIC 25 µg/mL.

N

N

O

R2

R1

NHXNH2

(2)

R1 = H, CH3, H; R2 = H, X= O, S

Synthesis of several new spiro indoline–based hetrocycles (3) was reported by Abdel-

rahman et al 3. The synthesized compounds 3a, 3b, 3c, 3d showed comparable activity

in which 3b, 3c revealed very high activity against S. subtilis (65.0, 75.0, 66.0, 42), E.

coli (54.0, 59.0), and A. niger (85.0, 70.0, 63.0, 58.0) with respect to the used

references Ampicillin and chloramphenicol.



NH

O

N

O

H2N

X

RO

(3)

R= CH3, C6H5, X= COOC2H5

Synthesis of new 1-alkyl/cyclohexyl-3, 3-diaryl-1’methyl-spiro [azetidine-2, 3’-

indoline]-2’, 4-diones (4) were reported by Singh et al 4. The synthesized compounds

4a, 4b, 4c showed the activity against the bacterial strains in which 4b with two 4-

methyl phenyl group showed activity against bacterial strains, B.subtilis, P.

aeruginosa, and S. aureus.

N

N

O

O

CH3

Ar

Ar

R

(4)

R= CH(CH3)2, CH(CH3)2, CHPh2 ,

Ar =Ph, 4-CH3C6H4, Ph

Synthesis of some new isatin derivatives (5) were reported by Patel et al 5. The

synthesized compounds 5(i-v) showed antimicrobial activities which were done by

disc diffusion technique which is shown in Fig.2. Among the compounds tested, the

compound with 5-Br substitution showed the most favorable antimicrobial activity

against A. niger, C. albicans.



N

N

O

N

HN

O

NH

O

R1

R

(5)

R= H, 5-Cl, 5-F, 5-Br, 5-CH3, R1= H

Synthesis of 3, 4’-dihydro-3-[2’-mercaptothiazolidine] indol-2-ones derivatives (6)

were reported by Pardasani et al 6. Synthesized compounds 6a, 6b, 6c showed

moderate activity against E. coli, S. facralus, R. solani and F. solani.

NH

N

S

SH

O

R

R= H, Br, NO2

(6)

The synthesis and antibacterial activity of two spiro [indole] thiadiazole derivatives

(7) were reported by Olomola et al 7. The compound was tested for antibacterial

activity against gram positive and gram negative bacterial strains. Compound showed

activity against 4- gram positive and 3-gram negative bacterial strains (better activity

than streptomycin, the reference standard).

N

S

N

N

CCH3

O

NH2

O

CH3

O

(7)

Synthesis of Mannich bases of norfloxacin with formaldehyde and several isatin

derivatives (8) were reported by Pandeya et al 8. The synthesized compounds 8(i-v)

were evaluated for their in vitro antibacterial activity against many pathogenic

bacterial strains (S. typhimurium, V. parahaemolyticus, V. cholerae0139 etc.). The



compound 8-iii (3.7 times) and 8-iv (4.8 times) were more active (0.018-0.61µg/mL)

to that of norfloxacin (1.22 µg/mL) against B.subtilis.

N

H2C NN

N

OCOOHF

CH2CH3

O

R1

R

(8)

R= H, Cl, Br, H, Cl

SO2NH

N

N

N

SO2NH

N

N

N

N

N

CH2N

OCH3

OCH3

OCH3NH2

SO2NH N

N

N

H3CO OCH3

R1 =

2.3.2.2. Anticancer

Synthesis of substituted 1H-indole-2,3 diones (isatin) (9) were reported by Vine et al

9. The synthesized compounds 9a, 9b, 9c showed the greater selectivity towards

leukemia and lymphoma cells over breast, prostate and colorectal carcinoma cell

lines. The most active compound 5, 6, 7 tribromo-isatin (9c) shown antiproliferative

at low micromolar concentration and also activated the effector capsases in a dose

dependant manner.

N

R1

O

R2

R3

R4

R5

R6

(9)

R1= O; R2 = H; R3 = Br; R4 = H, Br;

R5 = Br, NO2; R6 = H

Synthesis of isatin-benzothiazole analogs (10) were reported by Solomon et al 10

. The

synthesized compound 4-bromo-1-diethylaminomethyl 1H indol-2, 3-dion emerged as

most active compounds. The cytotoxic effect was 10-15 folds higher on cancer than

non-cancer cells.



N

O

O

NR1

R2

R

(10)

R = Br,

R1, R2 = CH2CH3

Synthesis of a series of functionalized isoindigos structurally related to meisoindigo

(1-methylisoindigo) (11) were reported by Wee et al 11

.The synthesized compounds

11a and11b [1-phenpropylisoindigo and 1-(p-methoxy-phenethyl)-isoindigo]

evaluated for antiproliferative activities on a panel of human cancer cells. These

compounds were more potent than meisoindigo and comparable to 6-bromoindirubin-

3’oxime on leukemic K562 and liver HuH7 cell were identified.

N

HN

O

O

R(11)

R = (CH2)3C6H5, (CH2)2C6H4(p- OCH3)

Synthesis of 3,5-dialkylamino substituted 8H,10H,15H, 15b(S)-2,3,6,7-tetrahydro-

1,5,3-dioxazepino[3,2-c]pteridine-7-one derivatives (12) were reported by Ge et al

12.The synthesized compounds 12a and 12b showed potential anticancer agent.

Preliminary results showed that they were active as inhibitors of the growth of murine

leukemia L1210 cells in vitro with IC50 values of 4-20 µM, comparable to Ellipticine

(reference drug).



N

N

O

O

N(C2H5)2

N(C2H5)2

ON

N

N

R

R1

(12)

R = H, CH3,

R1 = triethylamine, 1,4-dimethylpiperazine,

triethylamine

2.3.2.3. Antiviral

Synthesis of some new 6-(2-aminoethyl)-6-H-indolo [2, 3-b] quinoxalines (13) were

reported by Shibinskya et al 13

. The synthesized compounds 13(a-f) were screened for

the antiviral activity. The selective index (SI) value as the integral parameter of the

antiviral effectiveness was determined as the ratio of the CC50 to the IC50 (SI =CC50).

N

N

N

R

(13)

R= trimethylamine, pyrrolidine, 1-methylpiperazine,

1-methylpiperidine, morpholine

Synthesis of N-substituted isatin derivatives (14) were reported by Chen et al 14

. The

synthesized compounds 14a, 14b, 14c and d shown as potent and selective inhibitors

against SARS Coronaviral 3CL Protease with IC50 values ranging from 0.95 to 17.50

µM and isatin 14a exhibited more potent inhibition for SARS Coronavirus Protease.

N

O

OR1

R2

R3R4

R1 = R3 = H

R2 = CONH2, CN, I, NO2

R4 = 3,4,5-trimethylisoxazole,

2-methylbenzothiophene,

2-methylbenzofuran

(14)



Synthesis of 6H-indolo [2, 3-b] quinoxaline derivatives (15) were reported by Andrieu

et al 15

. The synthesized compounds 15a, 15b, 15c as antiviral agents and have shown

to interact with the minor groove of DNA.

N

N

N

R

(15)

R= CH3, CH2CH2N(CH3)2, H

Synthesis of a series of benzimidazole-isatin oximes (16) were reported by Sin et al

16. The synthesized compounds 16a, 16b and 16c showed the antiviral activity and as

inhibitors of respiratory syncytial virus (RSV) replication in cell culture with EC50

ranging from 18 to 50 µM, with excellent HLM stability.

N

N N

N

O

R

R1

O

(16)

R = CH2 CH2 F, CH3 CF3, CH2 CH3F

R = (CH2)4 OH, (CH2)4 OH, (CH2)3 SO2 CH3

The synthesis of a novel series of lamivudine prodrugs involving N4-substitution with

isatin derivatives (17) were reported by Sriram et al 17

. The synthesized compounds

17a and 17b showed in vitro antiretroviral activities and compound 17b was found to

be equipotent to lamivudine with EC50 of 0.0742 ± 0.04 µM.

N

N

O

N

N

N

R

O

O

S

OH

H(17)

R = H, F



Synthesis of a series of novel substituted isatin ribonucleosides (18) were reported by

Oliveira et al 18

. Synthesized compounds showed antiviral activity on HSV-1 infected

cells. Compounds 18a and 18c showed inhibitory activity and ribonucleoside 18c

showed 66% inhibitory activity on HIV-1 reverse transcriptase.

N

R1

R2

R3

O

O

O

OBZ

OBZ

OBZ

(18)

R1= H, Br; R2 = H, CH3, OBZ=o-benzoyl-D-ribofuranose;

R3 = H, Br


Synthesis of a series of 2-aryl-2, 5 dihydropyridazino [4,3-b]indol-3(3H)ones (19)

were reported by Palluotto et al 19

. The synthesized compounds 19a, 19b, 19c and 19d

showed anticonvulsant activity. The onsets of clonic and tonic seizures were

significantly reduced 45 min. after ip. (intraperitoneal) administration of derivatives

19(a-d) and comparable with standard drug (Flumazenil).

N

NN

O

R

R1

R2

R= H, R1 = p-Cl, p-Br, p-OCH3, p-Cl

R= H, CH3

(19)

Synthesis of a series of 2-aryl -2, 5-dihydropyridazino [4, 3-b] indol-3(3H) ones (20)

were reported by Campagna et al 20

. Synthesized compounds 20a, 20b and 20c were

evaluated for their good ability to prevent pentylenetetrazole (PTZ) induced seizures

in mice.



N

NN

O

X

H

(20)

X= H, Cl, Br

Synthesis of N-aryl/alkylidene-4-(1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) butanoyl

hydrazides/butanamides (21) were reported by Rajavendran et al 21

. Anticonvulsant

activity was determined using four animal models of seizures which included MES,

subcutaneous (sc PTZ) intraperitoneal Picritoxin (ip PIC) induced seizures threshold

test. Compounds were ineffective in MES test upto 300 mg/kg and showed protection

in sc PTZ screen included 21i, 21ii, and 21iii. These compounds were found to be

more potent when compared to standard drug phenytoin and ethosuximide, and were

effective at dose 30 mg/kg.

N

CONH

R1

R2

O

O

(21)

R1= 2-CH3, 3-Cl, R2 = 4-CH3, 2-CH3

R3 = CH3, R4 = 4-CH3-C6H4

Synthesis of 3-(4-chloro phenylimino)-5-methyl-1, 3-dihydro-indole-2-one (22) was

reported by Sridhar et al 22

. The synthesized compounds 22a, 22b, 22c were active in

MES test and compound 22b was found to be most active compound and showed 87%

protection at 100 mg/kg dose level with an ED50 value of 53.61 mg/kg.

N

N

O

R1

R3

R2

(22)

R1 = H, CH3, CH3, 4-methylphenyl,

4-chlorophenyl, 1-naphthyl,

R3 = H



Synthesis of 3-cycloalkanone-3,4-hydroxy-2-oxindoles derivatives (23) were reported

by Raj et al 23

. Synthesized compound 23a and 23b showed the MES test and PTZ

test. Compound 23a was active in PTZ seizure threshold test (PTZ), thus act as a

potential anticonvulsant.

N

O

X

HO

O

H(23)

X = Br, Cl

2.3.2.5. Antiinflammatory and Analgesic

Synthesis of a novel Schiff bases (24) were reported by Panneerselvam et al 24

. The

synthesized compounds were investigated for analgesic (Tail-immersion method) and

anti-inflammatory (Carrgenan induced paw oedema method). Among the synthesized

compounds 24a-d, the compound 24b, 24c and 24d exhibited remarkable analgesic

and anti-inflammatory activity when compared with standard drug (Pentazocin, 10

mg/kg, i.p. and Indomethacin 20 mg/kg).

N

N

O

N

R1

H

R

(24)

R = H, F, Cl, OCH3

R1= Cl, OCH3, NO2, OH

Synthesis of isatin derivatives (25) were reported by Mathues et al 25

. The synthesized

compounds 25a-f inhibited the cyclooxygenase (COX-2) enzymes in RAW 264.7

activated cells. The effect of isatin derivatives on COX-2 protein expression when

compared with vehicle treated groups. The incubation of cells with isatin derivatives

reduced COX-2 protein expression.

N

O

O

R(25)

R = H, 5-F, 6-Cl, 7-Cl,

4-Br, 5-I, 5-CH3



2.3.2.6. Antiplasmodial

Synthesis of a new class of 4-aminoquinoline derivatives (26) based on the natural

product isatin scaffold were reported by Chiyanzu et al 26

. The synthesized

compounds were screened for biological evaluation against three strains of the

malaria parasite plasmodium falciparum. These derivatives showed antiplasmodial

IC50 values in the ranges of 1.3 - 0.079 and 2.0 – 0.050 µM against a chloroquine –

sensitive (D10) and two resistant (K1 and W2) strains of P. falciparum. Quinoline

thiosemicarbazone derivatives (26a, 26b) showed better inhibition of falcipain-2

compared to the corresponding ketones.

N

D

O

H2C

R1

R2N N N

Cl

(26)

R1 = H, F

R2 = H,H

D = NNHC(S)NH2

Kumar et al. 27

designed and synthesised 3-methylene-substituted indolinones (27) as

falcipain inhibitors and antiplasmodial agents are described. These compounds react

readily with thiols via an addition-elimination mechanism, indicating their potential as

cysteine protease inhibitors. Several indolinones containing a Leu-i-amyl recognition

moiety were found to be moderate inhibitors of the Plasmodium falciparum cysteine

protease falcipain-2, but not of the related protease falcipain-3, and displayed

antiplasmodial activity against the chloroquine-resistant P. falciparum W2 strain in

the low micromolar range. Coupling a 7-chloroquinoline moiety to the 3-methylene-

substituted indolinone scaffold led to a significant improvement in antiplasmodial

activity.

N

O

R2

R1

NHHN CH3

O

R3

CH3

R1 = H, 5-Cl, 6-Cl, 7-Cl ; R

2 = H, CH3 ;

R3 = H, CH2CH(CH3)2, CH2CH2Ph, CH2Ph

(27)



2.3.2.7. Antitubercular

Synthesis of various substituted ciprofloxacin derivatives (28) were reported by

Sriram et al 28

. The synthesized compounds 28a, 28b, 28c and 28d shown better in-

vivo antitubercular activity against M. tuberculosis than ciprofloxacin in which

compound ‘28c’ decreased the bacterial load in spleen tissue with 0.76- log10

protection and was considered to be moderately active in reducing bacterial count in

spleen and compound ‘28d’ was found to be more active compound with MIC of 1.21

µM and was five times more potent than ciprofloxacin in-vitro (6.04 µM).

N

H2C N N N

O

F

COOH

O

R1

R

(28)

R= H, Cl, CH3, Br

R1= NNHCONH2

Aboul-Fadl et al. 29

designed and synthesised schiff bases of nalidixic acid

carbohydrazide and isatin derivatives (29). Structures of the synthesized derivatives

were confirmed on the bases of spectral methods of analyses. Anti-TB activity of the

synthesized derivatives was investigated against four Mycobacterium strains:

Mycobacterium intercellulari, Mycobacterium xenopi, Mycobacterium cheleneo and

Mycobacterium smegmatis. Modest anti-TB activity was observed within the

investigated compounds, however, compound 29f revealed potent anti-TB activity

with MIC 0.625 mg/ml, which is 20 times greater than the reference drug isoniazid,

INH, (MIC ¼ 12.5 mg/ml). A hypothetical pharmacophore model was built using

Molecular Operating Environment (MOE) program and 10 compounds structurally

related to the synthesized ones with reported anti-TB activity.

NO

N

HN N

N

CH3

CH3

O

O

R = H, Br; R1

= H, CH3, C2H5, CH2C6H5,

C3H7, OH

(29)



Kumar et al. 30

performed one-pot three-component domino reactions of cyclic mono

ketones, isatin and sarcosine/phenylglycine furnishing highly functionalised

dispiropyrrolidines in moderate yields. The reaction when performed with cyclic

amino acid, proline resulted in the dimerization of azomethine ylides. These

compounds have been screened for their in vitro activity against Mycobacterium

tuberculosis H37Rv (MTB) using agar dilution method. Among thirty eight

compounds screened, 1-methylpyrrolo( spiro[2.30]-5-bromooxindole)spiro[3.200]-

100-nitrosotetrahydro-400(1H)-pyridinone (30) was found to be the most active with

MIC of 1.98 mM against MTB and was 3.86 and 25.64 times more potent than the

standard first line TB drugs, ethambutol and pyrazinamide respectively.

NH

ONH

Ph

Ph

XY

O

(30)

X,Y = -CH2-CH2-, -CH2-CH2-CH2-,

-CH2-N(Me)-CH2, -CH2-N(CH2Ph)-CH2-;

R = H, CH3, Cl, Br; R1 = H, CH(CH3)2

R

R1

2.3.2.8. Antioxidant

Synthesis of 3, 3-bis (4-amino-2, 5-dimethoxyphenyl)-1, 3-dihydroindol-3-one

derivatives (31) were reported by Andreani et al 31

. The synthesized compounds 31a-c

were evaluated with 2-methods-the Briggs-Rauscher (BR) oscillating reaction method

that works in acidic conditions and the Trolox equivalent antioxidant activity (TEAC)

assay working at pH=7.4 and compounds 31a-c showed good chemical antioxidant

activity according to the design of these molecules that included a phenolic OH or

OCH3 groups in their structure.

R= CH3,CH3, 1-Chloro-4-ethylbenzene

R1= OH

R2= CH3, H, CH3

RN

NH

Cl

O

H3C

O

H3C

R1

R2

(31)



2.3.2.9. Anti- HIV

Synthesis of a series of isatin β-thiosemicarbazone derivatives (32) were reported by

Bal et al 32

. The synthesized compounds 32iii, 32iv, 32vi showed significant anti-HIV

activity in HTLV-IIIB strain in the CEM line where upon compound 32vi was found

to be the most active compound with an EC-50 value of 2.62 µM and selectivity index

of 17.41.

N

N

O

N

H

C S

C2H5

R

NC2H5

(32)

R = N- benzyl-N-methyl (phenyl)methanamine,

dimethylamine, 4-methylpiperazine,

4-ethyl-7-fluoro-1,4-dihydro-6-(4-methylpiperazin-1-yl)

-1-oxonaphthalene-2-carboxylic acid, 4-(4-nitrophenyl)piperazine,

1-(3-(trifluoromethyl)phenyl)piperazine

Novel oxindole derivatives bearing substituted cyclopropane ring (33) have been

designed by Kumari et al. 33

on the basis of docking studies with HIV-1 RT using the

software DS 2.5 and synthesized as probable NNRTIs against HIV-1 using

rhodium(II) acetate-catalyzed stereoselective cyclopropanation reaction. The

cyclopropane isomer, having trans relationship with respect to carbonyl of lactam

moiety and functional group on the cyclopropane ring, was the major product in all

cases along with a small amount of cis and methylene products. The trans isomers

interacted well with HIV-1 RT through H-bonding with amino acids, like Lys101,

Lys103, His235, Tyr318, constituting the non-nucleoside inhibitor binding pocket

(NNIBP) during docking experiments. However, the compounds showed very little

activity when subjected to in vitro anti-HIV-1 screening using b-galactosidase assay

(TZM-bl cells) and GFP quantification (CEM-GFP cells). The very low level of in

vitro HIV inhibition, in comparison to predicted EC50 values on the basis of

computational studies, during CEM-GFP screening using AZT as positive control

indicated that probably the HIV RT is not the viral target and the molecules work

through some different mechanism.



NH

OR1

H

H

H

R

NH

OH

R1

H

H

R

R = H, NO2, OCF3, CH3; R1 = CH2OH,

CH2Cl,

(33)

A series of novel 5-substituted-1-(arylmethyl/alkylmethyl)-1H-indole-2,3-dione-3-(N-

hydroxy/methoxy thiosemicarbazone) analogues (34, 35) were synthesized and evaluated

by Banerjee et al. 34

for their anti-HIV activity and anti-tubercular activity in both log

phase and starved cultures. The compound 2-(1-{[4-(4-chlorophenyl)tetrahydropyrazin-1

(2H)-yl]methyl}-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-yliden)-N-(methyloxy)

hydrazine -1-carbothioamide displayed promising activity against the replication of HIV-

1 cells (EC50 1.69 mM). In anti-mycobacterial screening it proved effective in inhibiting

the growth of both log phase (MIC 3.30 mM) and starved (MIC 12.11 mM) MTB

cultures. Isocitrate lyase enzyme having momentous implication in persistent TB was

shown to be inhibited by 1-cyclopropyl-6-fluoro-7-[4-{[5-methyl-3-((Z)-2-

{[(methyloxy)amino]carbothioyl}hydrazono)-2-oxo-1H-indol-1(2H)-yl]methyl}

tetrahydropyrazin-1(2H)-yl]-4-oxo-1,4-dihydroquinoline-3- carboxylic acid with 63.44%

inhibition at 10 mM.

N

O

R1

R1

N NH

NHOH

S

N

O

R1

R1

N NH

NHOCH3

S

(34) (35)

R1 = Cl, F, CH3 ; R1 = —N(CH3)2, —N(C2H5)2,

N O, N N N NCl,



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