http://informahealthcare.com/enz ISSN: 1475-6366 (print), 1475-6374 (electronic) J Enzyme Inhib Med Chem, Early Online: 1–13 ! 2014 Informa UK Ltd. DOI: 10.3109/14756366.2014.930454 REVIEW ARTICLE Quinoline and quinolones: promising scaffolds for future antimycobacterial agents Sandeep Singh, Gurpuneet Kaur, Veenu Mangla, and Manish K. Gupta Molecular Modeling and Pharmacoinformatics Lab, Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India Abstract Tuberculosis (TB) is still a major health concern worldwide. The increasing incidences of multi-drug-resistant tuberculosis (MDR-TB) necessitate the development of new anti-TB drugs acting via novel mode of action. The search of newer drugs for TB led to the identification of several quinoline-based antimycobacterial agents against both the drug-sensitive and MDR-TB. These agents have been designed by substituting quinoline scaffold with diverse chemical functionalities as well as by modifying quinoline/quinolone-based antibacterial drugs. Several of quinoline/quinolone derivatives displayed excellent antimycobacterial activity and were found free of cytotoxicity. This review highlights the critical aspects of design and structure–activity relationship of quinoline- and quinolone-based antimycobacterial agents. Keywords Antimycobacterials, infectious disease, MDR-TB, quinolines, TMC207 History Received 2 February 2014 Revised 5 May 2014 Accepted 22 May 2014 Published online 16 July 2014 Introduction Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the oldest life-threatening infectious diseases worldwide. TB affects people of all age groups; however, people with weak immune system are more prone to develop TB. According to World Health Organization, approximately 8.7 million people were affected with TB and 1.4 million died from TB in 2011. Over 95% of deaths occur in countries with lower economy 1 . Patients with HIV infection and other compromised immune system are more prone to develop TB. At least one-third of the 34 million people with HIV infection worldwide are infected with M. tuberculosis, and they are 21–34 times more likely to develop active TB than people without HIV infection 1 . The isoniazid (INH), rifampicin, pyrazinamide and ethambutol are potent first- line antitubercular drugs (Figure 1). But, in current scenario, the treatment of TB using first-line antitubercular drugs becomes ineffective due to the emergence of multi-drug-resistant tubercu- losis (MDR-TB) and extensively drug-resistant strains of Mycobacterium (XDR-TB). Therefore, the development of newer antimycobacterial drugs based on scaffolds having the potential to inhibit the growth of M. tuberculosis is of current interest (Figure 2). TMC207 (a diarylquinoline) is a novel antitubercular drug and currently under the Phase II studies for the treatment of patients infected with MDR-TB (Figure 3) 2 . TMC207 acts via inhibiting the mycobacterial adenosine triphosphate (ATP) synthase in Mycobacterium and thereby presents a novel mechanism to control the growth of M. tuberculosis 3 . Potent bactericidal and sterilizing activity of TMC207 against M. tuberculosis and other mycobacterial species makes it an attractive drug candidate to fight against TB. In a Phase II clinical trial on patients with MDR-TB, TMC207 showed significant efficacy after 2 months of treatment and appeared to be safe and well tolerated 4 . Haagsma et al. 5 studied the selectivity of TMC207 towards M. tuberculosis ATP synthase over the eukaryotic homologue and found that TMC207 is free from ATP synthesis-related toxicity in mammalian cells. TMC207, when used alone or in combin- ation with existing antimycobacterial drugs, represented a promising future for the treatment of TB 6,7 . In 2012, it was approved by U.S. Food and Drug Administration as a new drug to treat MDR-TB 8 . The identification of TMC207 as a new class of antimyco- bacterial drug with a novel mode of action attracted the attention of medicinal chemists to explore quinoline as a potential scaffold to develop antimycobacterial drugs (Figure 2). Also, the fluoroquinolone class of antibacterial drugs like ciprofloxacin, ofloxacin, gatifloxacin and moxifloxacin has been used effectively as second-line drugs for the treatment of MDR-TB (Figure 3). These drugs target Mycobacterium DNA gyrase and are prescribed in combination with first-line and other second-line antimycobacterial drugs 9 . This further augmented the probability of finding new quinoline-based antimycobacterial drugs. Therefore, numerous quinoline derivatives and analogs have been synthesized and evaluated for their efficacy against drug-sensitive and multi-drug-resistant Mycobacterium. Some studies have come out with the identification of effective quinoline-based antimycobacterial agents without cytotoxicity. This article will highlight the design and structure–activity relationship (SAR) aspects of quinoline-based novel antimyco- bacterial agents. Address for correspondence: Manish K. Gupta, School of Pharmacy, Lloyd Institute of Management and Technology, Greater Noida, (UP), India. Tel: +91 1202320749. E-mail: [email protected]Journal of Enzyme Inhibition and Medicinal Chemistry Downloaded from informahealthcare.com by University of Toronto on 08/11/14 For personal use only.
J Enzyme Inhib Med Chem, Early Online: 1–13! 2014 Informa UK Ltd. DOI: 10.3109/14756366.2014.930454
REVIEW ARTICLE
Quinoline and quinolones: promising scaffolds for futureantimycobacterial agents
Sandeep Singh, Gurpuneet Kaur, Veenu Mangla, and Manish K. Gupta
Molecular Modeling and Pharmacoinformatics Lab, Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India
Abstract
Tuberculosis (TB) is still a major health concern worldwide. The increasing incidences ofmulti-drug-resistant tuberculosis (MDR-TB) necessitate the development of new anti-TB drugsacting via novel mode of action. The search of newer drugs for TB led to the identificationof several quinoline-based antimycobacterial agents against both the drug-sensitive andMDR-TB. These agents have been designed by substituting quinoline scaffold with diversechemical functionalities as well as by modifying quinoline/quinolone-based antibacterialdrugs. Several of quinoline/quinolone derivatives displayed excellent antimycobacterialactivity and were found free of cytotoxicity. This review highlights the critical aspects ofdesign and structure–activity relationship of quinoline- and quinolone-based antimycobacterialagents.
Received 2 February 2014Revised 5 May 2014Accepted 22 May 2014Published online 16 July 2014
Introduction
Tuberculosis (TB), caused by Mycobacterium tuberculosis, isone of the oldest life-threatening infectious diseases worldwide.TB affects people of all age groups; however, people with weakimmune system are more prone to develop TB. According toWorld Health Organization, approximately 8.7 million peoplewere affected with TB and 1.4 million died from TB in 2011.Over 95% of deaths occur in countries with lower economy1.Patients with HIV infection and other compromised immunesystem are more prone to develop TB. At least one-third of the34 million people with HIV infection worldwide are infected withM. tuberculosis, and they are 21–34 times more likely to developactive TB than people without HIV infection1. The isoniazid(INH), rifampicin, pyrazinamide and ethambutol are potent first-line antitubercular drugs (Figure 1). But, in current scenario, thetreatment of TB using first-line antitubercular drugs becomesineffective due to the emergence of multi-drug-resistant tubercu-losis (MDR-TB) and extensively drug-resistant strains ofMycobacterium (XDR-TB). Therefore, the development ofnewer antimycobacterial drugs based on scaffolds having thepotential to inhibit the growth of M. tuberculosis is of currentinterest (Figure 2).
TMC207 (a diarylquinoline) is a novel antitubercular drug andcurrently under the Phase II studies for the treatment of patientsinfected with MDR-TB (Figure 3)2. TMC207 acts via inhibitingthe mycobacterial adenosine triphosphate (ATP) synthase in
Mycobacterium and thereby presents a novel mechanism tocontrol the growth of M. tuberculosis3. Potent bactericidal andsterilizing activity of TMC207 against M. tuberculosis and othermycobacterial species makes it an attractive drug candidate tofight against TB. In a Phase II clinical trial on patients withMDR-TB, TMC207 showed significant efficacy after 2 monthsof treatment and appeared to be safe and well tolerated4.Haagsma et al.5 studied the selectivity of TMC207 towardsM. tuberculosis ATP synthase over the eukaryotic homologue andfound that TMC207 is free from ATP synthesis-related toxicityin mammalian cells. TMC207, when used alone or in combin-ation with existing antimycobacterial drugs, represented apromising future for the treatment of TB6,7. In 2012, it wasapproved by U.S. Food and Drug Administration as a new drug totreat MDR-TB8.
The identification of TMC207 as a new class of antimyco-bacterial drug with a novel mode of action attracted the attentionof medicinal chemists to explore quinoline as a potential scaffoldto develop antimycobacterial drugs (Figure 2). Also, thefluoroquinolone class of antibacterial drugs like ciprofloxacin,ofloxacin, gatifloxacin and moxifloxacin has been usedeffectively as second-line drugs for the treatment of MDR-TB(Figure 3). These drugs target Mycobacterium DNA gyraseand are prescribed in combination with first-line and othersecond-line antimycobacterial drugs9. This further augmented theprobability of finding new quinoline-based antimycobacterialdrugs. Therefore, numerous quinoline derivatives and analogshave been synthesized and evaluated for their efficacy againstdrug-sensitive and multi-drug-resistant Mycobacterium. Somestudies have come out with the identification of effectivequinoline-based antimycobacterial agents without cytotoxicity.This article will highlight the design and structure–activityrelationship (SAR) aspects of quinoline-based novel antimyco-bacterial agents.
Address for correspondence: Manish K. Gupta, School of Pharmacy,Lloyd Institute of Management and Technology, Greater Noida, (UP),India. Tel: +91 1202320749. E-mail: [email protected]
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Substituted quinolines
2,3-Disubstituted quinolines
Mistry et al. synthesized novel quinoline-based azetidinone (1)and thiazolidinone (2) analogs and evaluated them for antimyco-bacterial activity. The SAR in both series of compounds showedthat 4-chloro- and 4-fluoro-substituted analogs possess betterantimycobacterial activity (62.5 mg/mL against M. tuberculosisH37Rv; Rifampicin: 40 mg/mL) than 2/3-chloro-, 2/3-fluoro-,nitro- and methyl-substituted analogs (125–500 mg/mL).A 2-amino-5-methyl-thiazole-substituted thiazolidonone analogalso showed comparable antimycobacterial activity (3, MIC:62.5 mg/mL)10,11. Two series of phenoxy-linked quinoline (4) andbisquinoline (5) derivatives were synthesized and screenedin vitro for their activity against M. tuberculosis H37Rv. Thestudy showed that bisquinoline series of compounds possessesbetter antimycobacterial activity (5, MIC: 1.1–43 mM) comparedto quinoline derivatives (4, MIC: 11.8–55.6 mM). Among all the
Figure 2. Substitutions on quinoline todevelop new antimycobacterial agents.
NMe2
NN
HN
F
O
OH
O
Ciprofloxacin
NN
N
F
O
OH
O
O
Ofloxacin
NN
HN
F
O
OH
O
O
Gatifloxacin
N
O
OH
O
F
N
OMeHN
H
H
Moxifloxacin
N
HO
OMe
TMC207
Br
N1
2
3
456
7
8
Quinoline
Figure 3. Structure of quinoline, floroquinolones and TMC207.
O
NH
H2N
N
Isoniazid
NH
OH
HN
HO
Ethambutol
N
NNH2
O
Pyrazinamide
OH OH
NH
O
O
HO
OH
OH
NN
O
O
OO
O
H
N
Rifampin
Figure 1. Structure of first-line antimycobacterial drugs.
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compounds, the 5a and 5b were found to be the most active.The in vitro cytotoxicity (IC50) of 5a and 5b on mouseembryonic fibroblast cell line (NIH 3T3) was reported as 333and 887mM, respectively, indicating that 37a and 37b are notcytotoxic12.
N
OCl
SHR
1 2
R2/3/4 = Me, NO2, Cl
3
NN SH
S
N
O
N SH
S
N
ON
S
MeR
R = F, Cl, NO2
N
R
Ph
Ar
O
N
Ph
RN
R
Ph
Ar
O
Ac
54
R = H,ClAr = Ph, 4-Me/Cl/Br/OMe-Ph
1/2-Naphthyl, 4-PhC6H4
R Ar MIC(µg/mL)5a Cl 4-BrPh 2.25b Cl 3-BrPh 1.1
Antimycobacterial activity of 2-aryloxyquinolines (6) and theirpyrano[3,2-c]chromene (7) derivatives were assessed by Mungraet al. Among the synthesized compounds, 6a and 7a showed morethan 90% growth inhibition at the concentration of 260 and250mg/mL, respectively13. A series of 3-benzyl-6-bromo-2-methoxy-quinolines (8) and amides of 2-[(6-bromo-2-methox-yquinolin-3-yl)-phenylmethyl]-malonic acid monomethyl ester(9) were synthesized and evaluated for their antimycobacterialactivity. Substituted-3-benzyl-6-bromo-2-methoxy-quinoline ana-logs, that is, 8a, 8b, 8c and 8d, exhibited 94.2%, 99.5%, 92.5%and 100% growth inhibition of M. tuberculosis H37Rv, respect-ively, at a concentration of 6.25 mg/mL. However, their amidederivatives (9) showed poor activity (less than 22% growthinhibition)14. In the cytotoxicity study on murine macrophagecells, 8c showed 100% cell viability at the concentration of10mg/mL. Eswaran et al. reported the synthesis and antimyco-bacterial activity of 3-(N-substituted urea)quinolines (10) andtheir cyclized oxazoloquinoline derivatives (11). Some of thesecompounds displayed good activity (MIC: 1mg/mL) comparedwith standard INH and rifampicin (MIC: 1.5 and 0.5mg/mLrespectively). The SARs indicated that the methoxy-phenyl,3-chloro-phenyl and 4-fluoro-phenyl substituents at R-positionare essential for activity. The cyclization of 3-(N-substitutedurea)quinolines (10) to oxazoloquinolines (11) also improved theactivity15.
R3 = H,Me
R3
R1 = H,Me,OMe
R2 = H,Me,Cl
R1
R1 R2 R3
R2
R2
NH2
O
O
N O N
O
R1
N
CHO
O
6
7
6a H H -7a Me Cl H
N
Br
O
R
8
N
Br
O
O
R1
O
O
9
R8a Imidazolyl
8b Pyrazolyl
8c 6-Amino-chromen-2-one
8d 1-(3-Trifluoromethyl-phenyl)-piperazinyl
N
OH
NH
OHN
R
R = 2-OMePh, 3-ClPh, 4-FPhR1 = H, F R2 = F, H
10
N
NO
HN R
11
R1
R2
R1
R2
2,4-Disubstituted quinolines
Nayyar et al. reported synthesis, antimycobacterial activity and3D-QSAR studies on two series of 4-(adamantan-1-yl)-2-substituted quinolines, namely 4-adamantan-1-yl-quinoline-2-carboxylic acid N0-alkylhydrazides and N0,N0-dialkylhydrazides(12) and 4-adamantan-1-yl-quinoline-2-carboxylic acid alkylide-nehydrazides (13). On activity evaluation against M. tuberculosisH37Rv, the compounds of these series displayed moderate-to-goodantimycobacterial activity in the MIC range of 1.0–6.25 mg/mLcompared with INH (MIC: 1mg/mL). For 4-adamantan-1-yl-quinoline-2-carboxylic acid N0-alkylhydrazides andN0,N0-dialkylhydrazides (12), the SAR suggested that five- andsix-membered ring or aryl substituents at R1 and a hydrogen at R2
are favorable for the activity. In 4-adamantan-1-yl-quinoline-2-carboxylic acid alkylidenehydrazides (13), the substitution withsmall aryl/heteroaryl rings exhibited better activity than otherbulkier substituents. The comparative molecular field analysis(CoMFA) indicated that the branched chain and cycloalkylsubstituents are favored on the hydrazine nitrogen (12) andphenyl/quinoline substituents are favored on hydrazone nitrogen(13). Also, small electronegative substituents are conducive forthe activity. Compound 13a was identified as the most potentcompound which exhibited 99% inhibition with the MIC of1mg/mL, equivalent to INH (MIC: 1mg/mL; 99% inhibition)16.
R2 = H, C3H7, C3H4-PhR1 =m/p F-Ph;
R2
R2 RR1
R1N
HN
N
O
N
HN
N
O
R
12 13
Activity(µg/ml) Activity(µg/ml)
12a mF-Ph H12b C6H11 H12c C5H9 H 3.125
3.1253.125
12d C3H7 C3H7 6.25
13a oCI-Ph13b Ph13c 4-OMePh 6.25
1.03.25
13d 2, 4-CF3Ph 6.2512e C3H6-Ph C3H6-Ph 6.25
DOI: 10.3109/14756366.2014.930454 Quinoline and quinolones 3
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The further development of 4-(adamantan-1-yl)-2-substitutedquinolines led to the development of four series of antimyco-bacterial compounds, namely: {1-[N0-(4-adamantan-1-yl-quin-oline-2-carbonyl)hydrazinocarbonyl]alkyl carbamic acidtert-butyl esters (14); 4-adamantan-1-yl-quinoline-2-carboxylicacid N0-(2-aminoalkyl)hydrazides (15); methyl 2-[4-(adamantan-1-yl)-2-quinonylcarboxamido]alkanoates (16) and N2-[1-hydrazi-nocarbonylalkyl]-4-(adamantan-1-yl)-2-quinolinecarboxamides(17)17. In this study, 14a, 14b, 14c, 16a and 16b were identified aspotent analogs and showed 99% inhibition of M. tuberculosisH37Rv at the concentration of 3.125 mg/mL. Compound 17adisplayed best activity (99% inhibition) against drug-sensitive M.tuberculosis H37Rv strain at 1.00 mg/mL, comparable to standarddrug INH used in this study (INH: 99% inhibition at MIC of 1mg/mL). The SAR of series 14 and 15 indicated that the presence of t-Boc [–NHCO2C(CH3)3] group imparts higher potency whencompared to the compounds with free amino group at the sidechain. For example, 14a showed 99% inhibition at 3.125 mg/mL,while 15a showed only 56% inhibition at 6.25 mg/mL. Also, inseries 16 and 17, the analogs conjugated with basic hetero-aromatic residue like L-histidine and highly cationic L-arginineresidue were found more potent when compared to the analogsconjugated with hydrophobic and other residues. All thecompounds, namely 14a, 14b, 14c, 16a, 16b and 17a werefound to be noncytotoxic up to the concentration of 50 mg/mL onmammalian kidney fibroblast (Vero) cells. The 3D-QSAR studysuggested that aromatic amino acid side chains bearing anelectropositive group or aliphatic side chains with electronegativesubstitutions would be favorable for antimycobacterial activity.Also, bulkier groups are detrimental for the activity due to stericeffect17.
R
NH
N
NH
14a
(CH2)3NHC(=NH)NH2 (CH2)3NHC(=NH)NH2
(CH2)3NHC(=NH)NH214b
14c
R
16aN NH
16b
17aN
HN
R
O
14
16
17
-NHCOCHNHBoc
R
R
-CHCOOMe
R
R
15
NH
15a
-NHCOCHNH2
-CHCONHNH2
3,4-Disubstituted quinolines
Thomas et al. reported the synthesis and antimycobacterialactivities of three series of 4-hydroxy-8-trifluoromethyl-quinolinederivatives, i.e. 4-hydroxy-8-(trifluoromethyl)quinoline-3-carbo-hydrazone (18), 2-{[4-hydroxy-8-(trifluoromethyl)quinolin-3-yl]carbonyl}hydrazinecarbothioamide (19) and 8-(trifluoro-methyl)quinolin-3-yl]carbonyl}-hydrazinecarboxamide (20)against drug-sensitive and MDR strains of Mycobacterium. Theevaluation of the activity of these compounds was carried outagainst different Mycobacterium strains. In comparison withINH and rifampicin, some of the synthesized compoundsdisplayed good activity against drug-sensitive and MDR strainsof Mycobacterium in comparison with INH and rifampicin18.Eswaran et al. reported the synthesis and antimycobacterialactivity of new quinoline derivatives and highlighted the effect ofsubstituted hydrazones at position C-3 of the quinoline (21). Fewcompounds have shown good antimycobacterial activity in MICranging from 0.625 to 1.25mg/mL against M. tuberculosis.The SAR indicated that 3-pyridyl, 3-(1,1,2,2-tetrafluoro ethox-y)phenyl, octyl, 2-fluoro-phenyl and 4-fluoro-phenyl at R1
position improve the activity while 5-bromo-thiophene,5-fluoro-2-hydroxy phenyl, 2-fluoro-4-methoxy-phenyl,
3-(methylthio)propyl and 4-methoxy-phenyl decrease the activity.Also, (3R)-3-amino-N,N-dimethyl-4-(phenylthio)butanamidemoiety at positions C-4 of quinoline skeleton showed profoundeffect of antimycobacterial activity. Compounds 21a and 21bwere identified as the most active compound with a MIC of0.625mg/mL and found to be nontoxic up to 62.5 mg/mL whentested on mammalian Vero cell lines19.
N
CF3
CF3
OH O
NH
N R
N
OH O
NH
HN NHR
X
18
19(X=S)
20(X=O)
R MIC (µg/ml)
MTB MS MF MDR-TB18a 5-OMe-1H-indole-3-carbaldehyde 0.625
Three series of quinoline-4-yl-1,2,3-triazoles possessing substi-tuted amides (22), sulphonamides (23) and amidopiperazines (24)were developed and evaluated for their antimycobacterial activ-ity20. All three series of compounds displayed moderate-to-goodactivity against M. tuberculosis (MIC: 0.625–1.25 mg/mL)compared with INH and rifampicin (MIC: 0.7 and 0.5 mg/mL,respectively). The SAR indicated that acetyl, methoxy, fluoro andtrifluoromethyl groups increase the activity while cyclo-butyl and2-chloro-benzoyl decrease the activity20. Thomas et al. alsodeveloped two series of hybrid quinoline-oxazolidinone mol-ecules (25, 26) as enoyl-ACP reductase ligands and antimyco-bacterial agents using structure-based drug design. It wasobserved that in both series of molecules, smaller groups likemethyl and dimethylamino at R-position are favorable for theactivity (MIC: 0.625 mg/mL) while bulkier groups such as4-ethylpiperazinyl, 4-acetylpiperazinyl and 4-isopropylpiperazinylare detrimental for the activity (MIC: 5–10mg/mL)21.
22
23
24
R = Ac, 4-F/Me/CF3-benzoyl, 4-MePh
22a
22b
22c
23a
PI(%)(mg/ml)
92
90
9623b
87
24a 91
24b 90
24c 92
N
MeO
N
N
N
Z
N N
R
O
Z R
a
b
c
-CO-pF-Ph
-CO-pMe-Ph
92
d -CO-pOMe-Ph
-CONHCHR2
-CH2NHSOR2
-COCH3
N
MeO
N
ONH
R
O
O
25
N
MeO
26
HN
O
N
OO R
R = Me, 4-CF3Ph, -N(Me)2
Carmo et al. reported the synthesis and antimycobacterialactivity (M. tuberculosis H37Rv) of 4-amino-7-chloroquinolines
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(27) and their platinum complexes (27a). However, thesecompounds (27) showed poor activity (MIC: 12.5–250 mg/mL)compared to the standard drug INH (0.03 mg/mL). Also, plat-inum-complexed compounds (27a) did not award any improve-ment in activity22. These compounds were found to be cytotoxicon mouse peritoneal macrophages (cytotoxic IC50: 6.90–13.36mg/mL).
Candea et al. synthesized a series of 7-chloro-4-quinolinylhy-drazones (28) as antimycobacterial agents. Some of thesynthesized compounds displayed moderate-to-good activity(MIC: 2.5 to 6.25 mg/mL) compared with standard drug etham-butol (MIC: 3.25 mg/mL). The SAR indicated that the compoundswith fluoro, chloro, hydroxy and methoxy groups possess goodactivity while bromo, nitro and cyano analogs showed decreasedactivity. These compounds were evaluated for their cytotoxicitiesby Mosmans’s assay on BCG-infected macrophages cell line J774.In this assay, 28a showed 100% cell viability at the dose of100mg/mL and thus found to be noncytotoxic to the host cells inthe effective concentrations (MIC 2.5 mg/mL) to inhibit thegrowth M. tuberculosis23. De Souza et al. studied the effect ofnumber of carbon in intermediate chain between two nitrogenatoms (as shown in 29) of 4-amino-quinolines on the antimyco-bacterial activity (29). The compounds with two to four carbonlength showed poor activity (MIC: 100mg/mL). Further incrementin the number of carbon, namely six, eight and ten carbons, led tothe significant increase in activity as shown by MIC of 25.0, 6.25and 3.12 mg/mL, respectively. The number of carbon atoms inintermediate chain is directly associated with the hydrophobicityof the compounds (log P), and hence contributing for higheractivity24.
Novel quinolyl-hydrazone derivatives (30) and their antimy-cobacterial activity were reported by Gemma et al. Thesederivatives displayed moderate-to-good antimycobacterial activ-ity (MIC: 0.6 to 10.0 mM) when compared with standard INH(MIC: 0.36 mM). Two derivatives 30a and 30b have shown 100%growth inhibition at the MIC of 0.6mM. In vitro cytotoxicity(IC50) of 30a and 30b in the Vero cell line was found to be0.45mg/mL (SI: 2.27) and 0.21 mg/mL (SI: 1.05), respectively.SAR indicated that functionalities at both the quinoline (R2) andarylhydrazone moiety (R3) modulate the antimycobacterial
activity. Among the quinoline substituents, the 7-OMe is favor-able for antimycobacterial activity, especially when coupled to anaphthyl ring at the hydrazone moiety. Based on the structure–activity pattern, authors suggested that the electronic effects of thequinoline-pharmacophore and the overall lypophilicity of themolecule play an important role in determining optimalantimycobacterial activity25. Antimycobacterial activity ofsubstituted quinolinyl-4-chalcones (31) and quinolinyl-4-pyrimi-dines (32) were reported by Sharma et al. Quinolinyl-chalcones(31a and 31b) showed excellent activity as shown by MIC of3.12 mg/mL compared to antimycobacterial drug pyrazinamide(MIC 50.0 mg/mL). Quinolinyl-chalcones also appeared to bebetter than quinolinyl-pyrimidines (32a and 32b, MIC: 12.5 mg/mL). Compounds 31a and 31b were found to be noncytotoxicwhen tested for cytotoxicity against Vero and MBMDM cell lines(IC50431.2 mg/mL)26.
Parekh et al. reported the synthesis and antimycobacterial activityof phenyl pyrazolone-substituted 1H-benzo[g]pyrazolo[3,4-b]quinoline-3-yl amine derivatives (33). These derivativesshowed moderate to poor activity (62.5–1000 mg/mL) againstM. tuberculosis H37Rv. Two derivatives 33a and 33b displayedcomparable antimycobacterial activity (MIC: 62.5 mg/mL) withthe standard rifampicin (MIC: 40 mg/mL). Among variousinhibitors, the chloro-substituted derivatives (mono or dichloro)exhibited better activity than methyl- or sulfonyl-substitutedonce27. Karthikeyan et al. reported 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles (thienoindole, 34) as a novel antimycobac-terial agent28. Balamurugan et al. designed a new class ofantimycobacterial agents 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines series; 35) by incorporating the pharmacophoricfeatures of TMC207 and thienoindole (Figure 4). Among thesynthesized compounds, 35a (MIC: 1.76 mg/mL) and 35b(MIC: 0.95 mg/mL) showed 6- and 12-fold higher activityagainst MDR-TB than standard drug INH (MIC: 11.38mg/mL).The SAR indicated that fluoro-, chloro- and nitro-substitutedinhibitors possess better antimycobacterial activity than
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methyl-phenyl- or 1-naphthyl-substituted analogs. Also, at C-7position (R2), the presence of chlorine atom considerablyimproved the activity. It may be suggested that electron-withdrawing substituents at R1 and R2 positions are conducivefor the activity29.
N NH
N
N N
HN NN
R
CH3
R33a 2,5-dichloro33b 3,4-dichloro
R=4-Me, 4-SO3H, 2,5/3,4-diCl
Antimycobacterial activity of a series of novel isomerichexahydro-2H-pyrano[3,2-c]quinoline analogs (36) was reportedby Kantevari et al.30. These analogs were designed by combiningthe hexahydro-2H-pyrano[3,2-c]quinoline scaffold with benzofur-obenzopyran pharmacophores (Figure 5). In in-vitro activityevaluation, the halogen-substituted analogs were found to be moreactive than unsubstituted/methyl/methoxy-substituted analogs.Among halogen-substituted analogs, the maximum activity wasobserved in fluoro analogs (R¼F, X¼N–CH3; MIC: 3.13 mg/mL; M. tuberculosis H37Rv), similar to that of ethambutol(MIC: 3.13 mg/mL). The isomeric analogs showed similaractivity30.
Quinoline derivatives derived from drugs
Derived from mefloquine
Mefloquine (antimalarial drug, Figure 6) targets ATP synthase inM. tuberculosis and possesses weak antimycobacterial activity(MIC for M. tuberculosis H37Rv: mefloquine 33mM; ethambutol15.9 mM)31. TMC207 also acts on the proton pump ofM. tuberculosis ATP synthase and possesses excellentpotency against drug-sensitive and drug-resistant strains ofMycobacterium3. Therefore, Chitra et al. proposed new anti-mycobacterial compounds by incorporating the chemical featuresof both TMC207 and mefloquine. The three new series of2-aryl-3-heteroarylthioquinolines, that is, 2-aryl-4-phenyl-3-qui-nolyl(5-methyl-1,3,4-thiadiazol-2-yl)sulfides (37), 1,3-benzothia-zol-2-yl [2-aryl-4-phenyl-3-quinolyl]sulfides (38) and 2-aryl-4-phenyl-3-[(2-phenyl-2H-1,2,3,4-tetraazol-5-yl)sulfanyl]quinoline(39) bearing pharmacophoric features of TMC207 and meflo-quine (Figure 6), were synthesized and evaluated for theirantimycobacterial activity32. The study showed that compoundsof series 37 possess superior antimycobacterial activityprofile (MIC: 3.2–30.4 mM) than compounds of series 38(MIC: 5.9–55.9 mM) and 39 (MIC: 23.3–54.6 mM). The twocompounds 37a and 37b exhibited an MIC of 3.2 and 3.5mM,respectively, for M. tuberculosis H37Rv and showed betteractivity than ciprofloxacin (MIC: 4.7mM) and ethambutol(MIC: 7.6mM). The in vitro cytotoxicity (IC50) of compounds37a and 37b on mouse embryonic fibroblasts cell line (NIH 3T3)was reported as 1263 and 2050 mM, respectively, indicating that
Figure 4. Design of 2,9-diaryl-2,3-dihy-drothieno[3,2-b]quinolines (35).
Figure 5. Design of hexahydro-2H-pyrano[3,2-c]quinoline analogs (36).
Hexahydro-2H-pyrano[3,2-c]quinoline
NH
OH
H
R
H
NH
OH
H
R
H
O
O
X36
Benzofurobenzopyran
X = O, N-MeR = H, Me, OMe, F, Cl, Br
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37a and 37b are not cytotoxic to the normal fibroblasts(NIH 3T3). In compounds of series 37, for aryl groups, theorder of activity was 4-BrC6H444-ClC6H444-PhC6H442-naphthyl44-MeOC6H444-MeC6H44C6H5. In all three series,the presence of halogens in aryl ring at C-2 position augmentedthe activity32.
Goncalves et al. designed two series of mefloquine–oxazoli-dine analogs (40 and 41) by condensing the mefloquine with aryland heterocyclic aldehydes (Figure 7). The study was designed toevaluate the effect of (a) the introduction of conformationalrestriction in the rotation of the piperidinyl ring of mefloquine bythe construction of an oxazolidine ring and (b) influence ofsubstituted aryl/heteroaryl functions attached to the oxazolidinering on the antimycobacterial activity (Figure 7). The compoundswere evaluated for their activity against M. tuberculosisH37Rv and M. tuberculosis T113. Compounds 40a and 41a
exhibited approximately 2.7 times more potency (MIC: 11.9and 12.1 mM, respectively) than mefloquine (MIC: 33.0 mM) inboth strains. They also displayed higher activity than ethambutol(MIC: 15.9 and 61.2 mM for M. tuberculosis H37Rv and T113,respectively). In Mosmans’s cytotoxicity assay on MurineMacrophages Cells, 40a and 41a showed 100% cell viabilityat the dose of 100 mM. The study showed that the electronicnature of substituents in the aryl ring plays a significant roleon the antimycobacterial activity. Inhibitors having electron-releasing groups, such as hydroxy and methoxy groups,were more active than electron-withdrawing chloro or nitrogroups31,33.
Eswaran et al. designed four new series of hydrazine-linked-quinolines based on the structure of mefloquine (Figure 8).The compounds were screened against M. tuberculosis andMDR-TB. Most of the compounds possess moderate-to-good
Figure 6. Design of 37, 38 and 39.
N
OH
NMe2
OMe
TMC207
N
CF3
CF3
HONH
Mefloquine
N
Z
Ar
37 38 39
Br
N
Ph
SS
NN
Cl
N
Ph
SS
NN
Br
37a 37b
SS
N
SS
NN
Me
SN
NN
N
PhZ:
N
NO
CF3
CF3CF3
CF3CF3
CF3
Ar
N
HN
HO
N
NO
C
YX
R
ArCHO
Y
X
R
CHO
40 41
Ar = 2,3/3,4-ClPh2,3/2,3,4-OMePh
40a: Ar = 2,3-diOMePh
X= O, S Y= CH, NR= H, NO2, OMe, OH, Cl, Br
41a: R= NO2 X= S Y= CH
Figure 7. Design of mefloquine–oxazolidine derivatives (40 and 41).
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antimycobacterial activity (MIC ranging from 6.25 to 12.5 mg/mL) and were found to be more active than INH and rifampicin.Compounds 43a, 43b, 43c, 43d, 43e, 44a, 46a and 46b werefound to be two- and four-fold more potent than INH and RIF(MIC: 6.25 mg/mL; INH: 12.5 mg/mL; RIF MIC: 25 mg/mL).It was suggested that the good antimycobacterial activity of thesecompounds is attributed to the presence of heteroaryl groups,namely pyrazole, imid-azole and indole. Compound 46a showedexcellent antimycobacterial activity against both TB strains(MIC: 3.12 and 6.25 mg/mL, respectively). The authors suggestedthat the presence of electron-donating –CH3 group stabilize thepyrazole ring and thus make the 46a more active againstM. tuberculosis34.
Derived from fluoroquinolones
Senthilkumar et al. reported the synthesis of a new series offluoroquinolones (47) as antimycobacterial agents. These com-pounds were evaluated for their antimycobacterial activitiesagainst M. tuberculosis H37Rv, MDR-TB and M. smegmatis(MC2) as well as for their ability to inhibit the supercoilingactivity of mycobacterial DNA gyrase. Compound 47a was foundto be the most active compound in the series with MIC of 0.16,0.33 0.68 mM against MTB, MDR-TB and MC2, respectively(INH: 0.36, 45.57 and 45.57 mM, respectively). Compound47a also inhibited the supercoiling activity of DNA gyrase withan IC50 of 30.0 mg/mL. The SAR of this series reveals thatthe substitution of nitro group at C-5 position increasedthe antimycobacterial activity up to ninefold, while the
replacement of nitro group with amino group reduces the activity.Substitution pattern at C-7 demonstrated the following orderof activity: fused piperazines and piperidines4(thio) morpho-lines4substituted piperazines4substituted piperidines.It was suggested that the introduction of bulky lipophilicsecondary amines at C-7 position improved antimycobacterialactivity due to more penetration of these compounds intomycobacterial cells35.
In continuation, Senthilkumar et al. also reported novelfluoroquinolones by varying the substitution at N-1 and C-7positions (47). Some of these compounds displayed moderate-to-good activity for M. tuberculosis and MDR-TB in the MICrange 0.08–16.6 and 0.08–14.45 mM, respectively. Two com-pounds 47b and 47c possess excellent in vitro activity for M.tuberculosis and MDR-TB. The in vivo efficacy of bothcompounds in M. tuberculosis ATCC35801-infected mice wasfound to be comparable with gatifloxacin (GATI) and INH on adose basis. Analysis of the substitution pattern at C-7 revealedthat the order of antimycobacterial activity was substitutedpiperidines4substituted piperazines4fused piperazines andpiperidines4(thio) morpholines. Interestingly, the studyrevealed that the contribution of the C-7 position to theactivity was dependent on the substituent at N-1 and was inthe order of substituted piperidines4substituted pipera-zines4fused piperazines and piperidines4(thio) morpholineswhen N-1 was cyclopropyl or t-butyl and substitutedpiperidines4substituted piperazines� fused piperazines andpiperidines� (thio)morpholines when substitutions at N-1 was2,4-difluorophenyl36,37.
N
NH
HOH
Mefloquine
N
HNNH2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
42
N
HNN
R
43
N
HNNH
HNX
R
N
NNO
R
46
OF
R
43a
43b
N
NH
43c
NN
Cl
43d
NHN
43e
44a
46a Me
46bO
O
6.25 6.25
6.25 6.25
6.25 6.25
6.25 6.25
3.12 6.25
3.12 6.25
3.12 6.25
6.25 6.25
MTB MDR-TB
MIC (mg/mL)
R= alkyl, aryl, heteroaryl
44X=O
45X=S
Figure 8. Design of hydrazine-linked-quinolines based on the structure of mefloquine.
8 S. Singh et al. J Enzyme Inhib Med Chem, Early Online: 1–13
Dinakaran et al. studied the antimycobacterial activity profileof various 2-(substituted)-3-fluoro/nitro-5,12-dihydro-5-oxoben-zothiazolo[3,2-a]quinoline-6-carboxylic acid derivatives (48) onM. tuberculosis H37Rv and MDT-TB and their efficacy to inhibitthe supercoiling activity of DNA gyrase. The compoundsdisplayed moderate to promising activity against both strains.Among the synthesized compounds, 48a showed best activitywith MIC of 0.18 and 0.08 mM against MTB and MDR-TB,respectively. Compound 48a was found to be 2 and 570 timesmore potent than standard INH against MTB and MDR-TB,respectively (INH, MIC: 0.36 and 45.57 for MTB and MDR-TB,respectively). The structure–MTB activity relationship for thesubstitution pattern at C-7 showed that the order of activity wassubstituted piperidines4fused piperazines, pyrrolidine andpiperidines4substituted piperazines, (thio) morpholines. Withrespect to the substitutions at R1, fluoro-substituted inhibitorswere found to be more active than nitro-substituted38. In anotherwork, Dinakaran et al. synthesized and evaluated variousofloxacin derivatives for their antimycobacterial activity on M.tuberculosis and MDR-TB (49). The most active compound 49adisplayed excellent activity against M. tuberculosis and MDR-TBat the MIC of 0.19 and 0.09 mM, respectively, when compared tothe ofloxacin and INH. SAR showed that, for R1, the introductionof nitro group led to the 1.1- to 8.8-fold higher activity while theintroduction of amino group reduced the activity. The SAR for thesubstituents at R2 position follows activity order as: fusedpiperazines and piperidines4substituted piperidines� (thio) mor-pholines4substituted piperazines39.
Sriram et al. reported the antimycobacterial activity profile of7-substituted ciprofloxacin (CP) derivatives (50). The CP deriva-tives showed moderate-to-excellent activity, with the MIC rangingfrom 1.21 to 10.82 nM when compared with ciprofloxacin andmoxifloxacin (MIC: 6.04 and 1.94 nM, respectively). Somederivatives exhibited 100% growth inhibition of M. tuberculosisH37Rv at the concentration of 6.25 mg/mL. However in DNAgyrase inhibitory activity assay, none of the compound showedbetter activity than moxifloxacin. In in vivo study on C57BL/6female mice, 50a reduced the bacterial load in spleen tissue with0.76-log10 protections and was suggested to be moderately activein decreasing bacterial count in spleen40.
In continuation of previous work, Sriram et al. alsoreported the antimycobacterial activity profile of 7-substitutedgatifloxacin derivatives (51). The gatifloxacin derivatives exhib-ited 4–62 times more activity than gatifloxacin against MDR-TB(51, MIC: 0.05 to 0.78; gatifloxacin, 3.12 mg/mL). ForM. tuberculosis, only four compounds (51a, 51b, 51c and 51d)displayed better activity than gatifloxacin while others werefound to be equal or lesser active derivatives. Among theactive derivatives, 51d appeared as the most active one, withthe MIC of 0.0125 and 0.05 mg/mL for M. tuberculosisand MDR-TB, respectively. 51d also showed wild-typeM. tuberculosis DNA gyrase inhibitory activity, with an IC50 of3.0mg/mL, comparable with gatifloxacin. In the in vivo animalmodel (female CD-1 mice) 51d decreased the bacterial load inlung and spleen tissues with 3.62 and 3.76-log10 protections,respectively. Furthermore, all the derivatives were found to benontoxic up to 62.5 mg/mL, and 51d showed selectivity index(IC50/MIC) of more than 1250. It was suggested that increasingthe lipophilicity of side chain at C-7 position improved theantimycobacterial activity41.
N
O
CO2H
NH2
CO2HF
NNN
O
50
R1=H, Cl, Br, MeR2=O, =NNHCONH2, =NNHCSNH2
N
O
F
NNN
N
O
Me
NH
O
50a
R2R1
N
O
CO2HF
N
NN
R2
O
R1 OMe
Me
51
R1 R2
51a H =NNHCONH251b F =NNHCONH2
51c Cl51d Me
GATI
N SO2NHN
N
MTB MDR-TB
0.0125 0.050.1
0.10.1
0.1
0.10.78
0.2 3.12
MIC(µg/mL)
Zhao et al. found out interesting observations on theantimycobacterial activity of two types of fluoroquinolonederivatives. In the first type, C-7 position of fluoroquinolonewas substituted with various six-membered heterocyclic rings likepiperidine, morpholine and piperazine (52). In other type, variousbifunctional fluoroquinolone–hydroxyquinoline complexes (53)were prepared, which include 8-hydroxyquinoline derivatives of
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norfloxacin (53a), ciprofloxacin (53b) and ofloxacin (53c). Theirantimycobacterial activity against M. tuberculosis H37Rv wasreported as the percentage growth inhibition (GI%) at theconcentration of 6.25 mg/mL. Closure look on the activity ofcompounds 52f and 52g and their fluoro-substituted counterparts52a and 52b suggested that fluoro group at R1 position isimportant for the activity. For R3 substituents, 7-piperidinylderivative (52a) and 7-(3,5-dimethylpiperazinyl) derivative (52b)displayed 97% and 98% inhibition, respectively, and appeared tobe more active than 7-morpholinyl (52c), 7-(4-methylpiperazinyl)(52d) and 7-piperazinyl (52e) derivatives. Interestingly, 44%growth inhibition of M. tuberculosis by (7-[4-(8-hydroxyquinolin-2-ylmethyl)piperazin-1-yl] derivative) (53d) over 7-piperadinyl(52f) and 7-morphonyl (52g) suggested that metal-chelatingproperty of 8-hydroxyquinoline moiety is conducive antimyco-bacterial activity. For the bifunctional fluoroquinolone–hydro-xyquinoline complexes, norfloxacin (53a, 84% inhibition),ciprofloxacin (53b, 98%) and ofloxacine (53c, 98%) derivativeswere found to be more potent than 1-aryl congeners 53d and 53e,which showed only 44% and 47% M. tuberculosis growthinhibition, respectively42. Antimycobacterial potential of fluoro-quinolones (54) was also studied by Talath et al. However, thesecompounds showed only moderate antimycobacterial activity(MIC: 10mg/mL)43.
N
OCO2HF
N
ON
HNN
Me
Me
GI(%) R1 R3
R3R1
R2
52a 97 F
52b 98 F
52c 49 F
52d 0 F
52e 37 F
52f 6 H
52g 0 H
NN
Me
HNN
N
ON
52
R1 = H/FR2 = NO2/NH2
GI(%) R1
R1
R2
R2NOH
NN N
OCOOHF
53
53a 86 -CH2CH3 H
53b 98 H
53c 98
53d 44 H
53e 47 H
MeO
NO2
HNN
Me
Me
N
OH
R
R1
F
N
R2N
O O
R4
S
R3O O
NN
SH2N
54a H H H
54b Et H H H
R R1 R2 R3
54
Vavrikova et al. synthesized hydrazine-linked derivatives ofp-aminosalicylic acid (PAS, 55), ciprofloxacin (CP, 56) andnorfloxacin (NF, 57) and evaluated their antimycobacterialactivity against drug-sensitive (H37Rv) and MDR (MDR A8241) strains of M. tuberculosis. For MDR-TB, PAS-hydrazonesand CP-hydrazones exhibited better activity (MIC: 0.5 mg/mL)than INH, CP and NF alone (MIC: INH 1.0 mg/mL; PAS 0.25 mg/mL; CP: 1.5mg/mL; NF: 10mg/mL). For M. tuberculosis H37Rv,the CP-hydrazones appeared to be better (MIC: 1mg/mL) thanPAS-hydrazones and NF-hydrazones (MIC: 2–6mg/mL). Allhydrazones were found to be noncytotoxic for human hepatocytes,PBMC cells and human SH-SY5Y neuroblastoma cells (cytotoxicIC50: 0.03 to 1.28 mM)44.
R
O NH
N NR1R2 R1R2N- =
COOH
OH
HN
F
N N
O
COOH
N
F
N N
O
COOH
N
57 (NF)56 (CP)55 (PAS)R = 3/4-CF3, 2/3/4-F
Derived from ferroquine
Ferroquine (FQ, SSR97193), an antimalarial compound, alsopossesses moderate antimycobacterial activity (MIC: 10–15 mg/mL; M. tuberculosis MC2 7000)45,46. It is a hybrid of 4-amino-7-chloro-quinoline and ferrocene. Few ferrocenyl derivatives quin-oline–ferrocene hybrid (58) and ferrocene-based hydrazones(59–61) were developed by Mahajan et al. and evaluatedin vitro for their efficacy against Mycobacterium (M. tuberculosisMC2 7000). It was found that only quinoline–ferrocene hybrid(58) possesses good antimycobacterial activity (MIC: 2.5–5 mg/mL; M. tuberculosis MC2 7000) comparable to that of ethambutol(MIC: 1–2.5 mg/mL), while all ferrocene-based hydrazones (59–61) failed to show antimycobacterial activity (MIC4100mg/mL).It was suggested that the good antimycobacterial activity of 58may be attributed to the presence of the quinoline ring in theferrocenyl derivatives46.
N
Cl
HN
N
58
NN
NN
N
HN
NFe
Fe
HN
NFe
60
N
N
NN
MeO
HN
NFe
NN
NN
Me
59
61
NCl
NH
Fe
NMe
Me
FQ
Miscellaneous
Parmar et al. studied the antimycobacterial effect of quinoloneslinked with diazepinones (62). They synthesized a novel series ofquinolyldibenzo[b,e][1,4]diazepinones, and among the evaluatedcompounds, 62a and 62b showed 96% and 91% growth inhibitionactivity, respectively, for M. tuberculosis H37Rv at the
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concentration of 250mg/mL47. Manvar et al. studied theantimycobacterial potential of various hydrazides of substitutedquinolones (63) and coumarins (64). The quinolone analogsdisplayed three- to four-fold better activity profile (GI: 98–100%)compared to the coumarin analogs (GI: 17–25% at MIC56.25 mg/mL). The quinolone analogs with bromo, phenyl and methyl at R1
position impart excellent growth inhibitory activity (GI: 98–100%), while nitro, fluoro and dichloro groups compromised theactivity of quinolone analogs (GI: 60–89%). This may besuggested that hydrophobic substituents at R1 are favorable forthe growth inhibitory activity while electron-withdrawing sub-stituents are detrimental for the activity48.
HN
NHO
NH O
NH
NH
CH3CH3 H3C
H3C
H3C
H3C
O
N
H
O
62a 62b
HN
NH
RR
O
N O
62
R = H, Me
R1= H, Cl, Me
R2= H, Me
N O
O
NNH
R
R= H, Me
R1= 2/3-Ph, Me, Cl, NO2R2= 2/3/4-Cl, H, NO2
63
O O
O
NNH
Ph
R1= 2-NO2, 2-Cl, 2-Me
3-F, 3-Me, 4-F
64
R2
R2
R1
R1R1
Carta et al. reported 3-methyl-9-substituted-6-oxo-6,9-dihy-dro-3H-[1,2,3]-triazolo[4,5-h]quinolone-carboxylic acids andtheir esters (65) as a new class of antimycobacterial agentsagainst MDR-TB. Screening of these derivatives againstM. tuberculosis H37Rv and 11 other clinically isolated strains ofM. tuberculosis displayed MIC90 in the range of 0.5–3.2 mg/mL.65a was identified as the most effective derivative (MIC90: 0.5mg/mL) in comparison with rifampin (MIC90: 0.7–4.0 g/mL) againstall M. tuberculosis strains. Furthermore, 65a showed no cytotox-icity for both human macrophages and Hep-2 cells up to theconcentration of 50 mg/mL. The presence of alkyl substituents atN-1 position was found to be more favorable for the activity thanpropenyl, benzyl or phenylethyl groups. Also, free carboxylic acidderivatives appeared to be superior compared to esteranalogs49,50.
Kantevari et al. assessed the antimycobacterial activityof substituted aryl-tethered dihydro-6H-quinolin-5-ones (66),thiophenyl-tethered dihydro-6H-quinolin-5-ones (67) and theirmethyl hydroxyl analogs (68 and 69). In comparison witharyl-tethered dihydro-6H-quinolin-5-ones (66, MIC: 12.5 mg/mL), thiophenyl-tethered dihydro-6H-quinolin-5-ones dis-played better antimycobacterial activity (67, MIC: 3.13–6.25mg/mL). The substitution with chloro and bromo enhance theactivity while methyl and methoxy groups proved to bedetrimental for the activity. The hydroxyl methyl analogs(68 and 69) showed poor activity (MIC:425 mg/mL). The studyindicated that the antimycobacterial activity mainly dependsupon the lipophilicity of these compounds. The thiophenyl-tethered dihydro-6H-quinolin-5-ones (67; log P� 2.91 to 4.32)are relatively more lipophilic than aryl-tethered dihydro-6H-quinolin-5-ones (66; log P� 3.39 to 4.53). The hydroxylmethyl analogs possess least lipophilicity and poor activity(68 and 69; log P� 2.06 to 2.88)51. A new series ofN-arylaminobiquinoline derivatives (70) as antimycobacterialagents was reported by Shah et al. Among the tested compounds,70a and 70b displayed 87% and 85% growth inhibitory activity,
respectively, at the concentration of 6.25 mg/mL compared with98% activity of rifampicin52.
Exploration of chemical space around quinoline scaffold led tothe identification of several new series of compounds with notableantimycobacterial activity against drug-sensitive and MDR-TB.For instance, 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinoline 35a(MIC: 1.76 mg/mL) and 35b (MIC: 0.95 mg/mL) showed 6- and12-fold higher activity against MDR-TB than standard drug INH(MIC: 11.38mg/mL). Also, 4-hydroxy-8-(trifluoromethyl)quin-oline-3-carbohydrazone (18a–d) and 2-{[4-hydroxy-8-(trifluoro-methyl)quinolin-3-yl]carbonyl}hydrazinecarbothioamide (19a)appeared as 2–4 times more active against MDR-TB than INHand rifampicin, respectively. Among the compounds derived fromexisting drugs, 47a (a fluoroquinolone; MIC: 0.33 mM) appearedto be 138 times more active than INH against MDR-TB and alsoinhibited the supercoiling activity of DNA gyrase with an IC50 of30.0 mg/mL. Several of quinoline derivatives appear to be safewhen tested for their cytotoxicity. These studies also emphasizethe substitution patterns in quinoline and quinolone scaffolds toimprove their antimycobacterial activity against drug-sensitiveand MDR strains. It can be clearly substantiated that quinoline
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and quinolone are potential scaffolds to develop future anti-mycobacterial drugs. This systematic review will provide acomprehendible information to researchers to design and developpotent quinoline/quinolone-based antimycobacterial drugs.
Acknowledgements
Authors thank Chairman, ISF College of Pharmacy, Moga (PB), India, forhis valuable support and encouragement.
Declaration of interest
The authors have declared no conflict of interest.
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