Synthesis, in vitro and in vivo antimycobacterial activities of diclofenac acid hydrazones and amides

Various diclofenac acid hydrazones and amides were synthesized and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis. Preliminary results indicated that most of the compounds demonstrated better in vitro antimycobacterial activity (MIC: 0.0383-7.53 microM) than diclofenac (MIC: 21.10 microM) and ciprofloxacin (MIC: 9.41 microM). Among the synthesized compounds, 1-cyclopropyl-6-fluoro-8-methoxy-7-[[N4-(2-(2-(2,6-dichlorophenylamino)phenyl)acetyl)-3-methyl]-N1-piperazinyl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (5d) was found to be the most active compound in vitro with MIC of 0.0383 microM and was more potent than first line antitubercular drug isoniazid (MIC: 0.1822 microM). In the in vivo animal model 5d decreased the bacterial load in lung and spleen tissues with 2.42- and 3.66-log10 protections, respectively, at 25 mg/kg body weight.     

Gatifloxacin derivatives: synthesis, antimycobacterial activities, and inhibition of Mycobacterium tuberculosis DNA gyrase

Sixteen 7-substituted gatifloxacin derivatives were synthesized and evaluated for antimycobacterial activity in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB), and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. tuberculosis. Among the synthesized compounds, 1-cyclopropyl-6-fluoro-8-methoxy-7-[[[N4-[1'-(5-isatinyl-beta-semicarbazo)]methyl]3-methyl]N1-piperazinyl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (3d) was found to be the most active compound in vitro with an MIC of 0.0125 microg/mL against MTB and MTR-TB. In the in vivo animal model 3d decreased the bacterial load in lung and spleen tissues with 3.62- and 3.76-log10 protections, respectively. Compound 3d was also found to be equally active as gatifloxacin in the inhibition of the supercoiling activity of wild-type M. tuberculosis DNA gyrase with an IC50 of 3.0 microg/mL. The results demonstrate the potential and importance of developing new quinolone derivatives against mycobacterial infections.     

Evaluation of antimycobacterial and DNA gyrase inhibition of fluoroquinolone derivatives

The antimycobacterial activity (both in vitro and in vivo) and DNA gyrase inhibition of newly synthesized fluoroquinolone derivatives were tested against Mycobacterium tuberculosis H(37)Rv and Mycobacterium smegmatis, respectively. Among the synthesized compounds, compound F11 was found to exhibit the most potent in vitro antimycobacterial activity with a MIC value of 0.78 microg/ml, and a selectivity index of more than 80 while not being cytotoxic to the Vero cell line up to 62.5 microg/ml. When evaluated for in vivo antimycobacterial activity, compound F11 demonstrated a paramount decrease of bacterial load in lung and spleen tissues compared to the control and better than the standard drug ciprofloxacin.     

Novel ofloxacin derivatives: synthesis, antimycobacterial and toxicological evaluation

Thirty novel 9-fluoro-2,3-dihydro-8,10-(mono/di-sub)-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acids were synthesized from 2,3,4,5-tetrafluoro benzoic acid and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from mycobacteria. Among the synthesized compounds, 10-[2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active compound in vitro with MIC99 of 0.19 microM and 0.09 microM against MTB and MTR-TB, respectively. In the in vivo animal model also the same compound decreased the bacterial load in lung and spleen tissues with 1.91 and 2.91--log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 10-[(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active in the inhibition of the supercoiling activity of DNA gyrase with an IC(50) of 10.0 microg/mL. The results demonstrate the potential and importance of developing new oxazino quinolone derivatives against mycobacterial infections.     

Antimycobacterial activities of novel 2-(sub)-3-fluoro/nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid

Various 2-(sub)-3-fluoro/nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid derivatives were synthesized from 2-aminothiophenol by a five-step reaction, evaluated for in-vitro and in-vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC2), and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the thirty-four synthesized compounds, 2-(3-(diethylcarbamoyl)piperidin-1-yl)-)-3-fluoro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid (7l) was found to be the most active compound in vitro with MIC of 0.18 and 0.08 microM against MTB and MTR-TB, respectively. Compound 7l was found to be 2 and 570 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in-vivo animal model 7l decreased the bacterial load in lung and spleen tissues with 2.78 and 3.12-log10 protections, respectively, at the dose of 50 mg/kg body weight.     

Synthesis and antimycobacterial evaluation of newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids

Thirty-four newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids were synthesized from 1,2,3,4-tetrafluoro benzene and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase. Among the synthesized compounds, 7-(1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolin-2(1H)-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylic acid (13n) was found to be the most active compound in vitro with MIC of 0.16 and 0.33 microM against MTB and MDR-TB, respectively. In the in vivo animal model 13n decreased the bacterial load in lung and spleen tissues with 2.54 and 2.92-log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 13n also inhibited the supercoiling activity of mycobacterial DNA gyrase with IC(50) of 30.0 microg/ml.     

Synthesis and preliminary in vitro evaluation of antimycobacterial activity of new pyrrolo[1,2-a] quinoxaline-carboxylic acid hydrazide derivatives

New pyrrolo[1,2-a]quinoxaline-2- or -4-carboxylic acid hydrazide derivatives were synthesized from nitroaniline or 1,2-phenylenediamine, and evaluated in vitro for their antimycobacterial activity as part of a TAACF TB screening program. Two compounds 7c and 13 showed an interesting activity at 6.25 microg/mL against Mycobacterium tuberculosis H37Rv, with a 94 and 100 percentage inhibition, respectively.     

Synthesis of pyrazinamide Mannich bases and its antitubercular properties

A series of pyrazinamide (PAZ) Mannich bases has been synthesized by reacting PAZ, formaldehyde, and various substituted piperazines using microwave irradiation with the yield ranging from 46% to 86%. The synthesized compounds were evaluated for antimycobacterial activity in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB). Among the synthesized compounds, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-4-((pyrazine-2-carboxamido)methyl)piperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (17) was found to be the most active compound in vitro with MIC of 0.39 and 0.2 microg/mL against MTB and multidrug-resistant MTB, respectively. In the in vivo animal model 17 decreased the bacterial load in lung and spleen tissues with 1.86 and 1.66-log10 protections, respectively.     

Synthesis and antimicrobial activity of N¹-benzyl or N¹-benzyloxy-1,6-dihydro-1,3,5-triazine-2,4-diamines

The emergence and spread of multidrug-resistant strains of Staphylococcus aureus and Mycobacterium tuberculosis are generating a threat to public health worldwide. In the current study, a series of N(1)-benzyl and N(1)-benzyloxy-1,6-dihydro-1,3,5-triazine-2,4-diamine derivatives were synthesized and investigated for their antimicrobial activity against S. aureus, and Mycobacterium smegmatis which is taxonomically related to M. tuberculosis. Most of the compounds exhibited good activity against M. smegmatis as determined by comparison of diameters of the zone of inhibition of test compounds and standard antibiotics. Compound 7o showed potent antimycobacterial activity against M. smegmatis without mammalian DHFR inhibition liability. The results from this study indicate that 1-benzyl derivatives of 1,6-dihydro-1,3,5-triazine-2,4-diamines may be used as lead compounds for the discovery of antimycobacterial agents.     

Antifungal and antimycobacterial activity of 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives

1-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives were synthesized and tested for their in vitro antifungal and antimycobacterial activities. These imidazole derivatives showed an excellent antifungal activity against a clinical strain of Candida albicans and an interesting antitubercular activity against Mycobacterium tuberculosis H(37)Rv reference strain.     

Highly active antimycobacterial derivatives of benzoxazine

New 3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. The antimycobacterial activity increased with the replacement of the carbonyl group by the thiocarbonyl group in the starting 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-diones. The most active derivatives were more active than isonicotinhydrazide (INH). Free-Wilson analysis was also carried out and the activity contribution was examined.     

Synthesis and in vitro antitubercular activity of some 1-[(4-sub)phenyl]-3-(4-{1-[(pyridine-4-carbonyl)hydrazono]ethyl}phenyl)thiourea

Various isonicotinyl hydrazones were prepared by reacting isonicotinyl hydrazide [INH] with 1-(4-acetylphenyl)-3-[(4-sub)phenyl]thiourea and were tested for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv and INH-resistant M. tuberculosis using the BACTEC 460 radiometric system. Among the synthesized compounds, 1-(4-fluorophenyl)-3-(4-{1-[(pyridine-4-carbonyl)-hydrazono]ethyl}phenyl)thiourea (4d) was found to be the most potent compound with a minimum inhibitory concentration of 0.49 microM against M. tuberculosis H37Rv and INH-resistant M. tuberculosis. When compared to INH, 4d was found to be 3 and 185 times more active against M. tuberculosis H37Rv and INH-resistant M. tuberculosis, respectively, with a selectivity index of >300.     

Synthesis and antimycobacterial activity of 4-(5-substituted-1,3,4-oxadiazol-2-yl)pyridines

4-(5-Substituted-1,3,4-oxadiazol-2-yl)pyridine derivatives 1-12 were synthesized and evaluated for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against Mycobacterium tuberculosis H(37)Rv and five clinical isolates (drug-sensitive and -resistant strains). Compound 4 [4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine] was 10 times more active than isoniazid, 20 times more active than streptomycin, and 28 times more potent than ethambutol against drug-resistant strain CIBIN 112. Compound 5 [4-(5-heptadecyl-1,3,4-oxadiazol-2-yl)pyridine] showed the same behavior as compound 4. Both of the above structures bear a high lipophilic chain bonded to the 5-position of the oxadiazole moiety. This fact implies that there exists a contribution of lipophilicity, which could facilitate the entrance of these molecules through lipid-enriched bacterial cell membrane.     

Antimycobacterial activity of basic ethyl esters of alkoxy-substituted phenylcarbamic acids

A series of 124 basic ethyl esters of alkoxy-substituted phenylcarbamic acids with the alkoxy group in position 2, 3 or 4 on the phenyl ring, and basic substituents attached to the ethyl moiety in position 2, were evaluated for in vitro antimycobacterial activity against strains of Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. In vitro antimycobacterial activity becomes higher with increasing hydrophobic properties of the alkoxy groups. The p- and m-substituted derivatives were more active than the o-substituted ones. Direct relationship between the structure of the basic substituents and the activity was not found.     

Synthesis and antimycobacterial activity of 4-[5-(substituted phenyl)-4, 5-dihydro-3-isoxazolyl]-2-methylphenols

Compounds based on the isoxazoline moiety were screened for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37R (MTB), and INH (isoniazid) resistant Mycobacterium tuberculosis (INHR-MTB) using the agar dilution method and bactec 460. Among the synthesized compounds, 4-[5-(4-bromophenyl)-4,5-dihydro-3-isoxazolyl]-2-methylphenol (4l) was found to be the most active agent against MTB and INHR-MTB with minimum inhibitory concentration of 0.62 microM. When compared to INH, compound (4l) was 1.12 fold and 3.0 fold more active against MTB and INHR-MTB, respectively.     

Synthesis, antimicrobial and antimycobacterial evaluation of [2-(substituted phenyl)-imidazol-1-yl]-pyridin-3-yl-methanones

A series of [2-(substituted phenyl)-imidazol-1-yl]-pyridin-3-yl-methanones (1-11) were synthesized and screened for their antimicrobial and antimycobacterial activities. Further, a series of [2-(substituted phenyl)-benzimidazol-1-yl]-pyridin-3-yl-methanones (12-20) reported in our earlier study was also screened for their antimycobacterial activity. The antimycobacterial activity results indicated that [2-(4-Nitro-phenyl)-imidazol-1-yl]-pyridin-3-yl-methanone (8, minimum inhibitory concentration [MIC]?=?3.13 μg) was equipotent as standard drug ciprofloxacin and [2-(4-Nitro-phenyl)-benzimidazol-1-yl]-pyridin-3-yl-methanone (16, MIC?=?1.56 μg) was equipotent as standard drug ethambutol. The results of antimicrobial screening demonstrated that 2-[1-(Pyridine-3-carbonyl)-1H-imidazol-2-yl]-benzoic acid (compound 11, MIC?=?0.002 μg) was two times more effective than standard drug ciprofloxacin (MIC?=?0.004 μg) against tested bacterial strains and [2-(2,5-Dimethyl-phenyl)-imidazol-1-yl]-pyridin-3-yl-methanone (compound 3, MIC?=?0.005 μg) was equipotent to the reference compound, fluconazole against tested fungal strains.     

Synthesis and antimycobacterial evaluation of N-substituted 3-aminopyrazine-2,5-dicarbonitriles

A series of 14 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and two types of Mycobacterium avium. The series comprised of N-substituted 3-aminopyrazine-2,5-dicarbonitriles derived from 3-chloropyrazine-2,5-dicarbonitrile by nucleophilic substitution of chlorine by various non-aromatic amines (alkylamines, cycloalkylamines and heterocyclic amines). Noteworthy antimycobacterial activity against M. tuberculosis was found among the alkylamino derivatives, for example, 3-(heptylamino)pyrazine-2,5-dicarbonitrile inhibited M. tuberculosis at MIC=51 μmol/L. 3-(Hexylamino)pyrazine-2,5-dicarbonitrile inhibited M. kansasii at MIC=218 μmol/L. Basic structure-activity relationships are discussed. A comparison between calculated and experimentally determined lipophilicity parameters within the series is included.     

Synthesis and in vitro antimycobacterial activity of N1-nicotinoyl-3-(4'-hydroxy-3'-methyl phenyl)-5-[(sub)phenyl]-2-pyrazolines

A series of N1-nicotinoyl-3- (4'-hydroxy-3'-methyl phenyl)-5-(substituted phenyl)-2-pyrazolines were synthesized by the reaction between isoniazid (INH) and chalcones and were tested for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv (MTB) and INH-resistant M. tuberculosis (INHR-MTB) using the agar dilution method. Among the synthesized compounds, compound (i) N1-nicotinyl-3-(4'-hydroxy-3'-methyl phenyl)-5-(1'-chlorophenyl)-2-pyrazoline was found to be the most active agent against MTB and INHR-MTB, with minimum inhibitory concentration of 0.26 microm. When compared to INH-compound i was found to be 2.8- and 43.7-fold more active against MTB and INHR-MTB, respectively.     

Antimycobacterial compounds. Optimization of the BM 212 structure, the lead compound for a new pyrrole derivative class

Our work on antitubercular agents led to the identification of BM 212 as a lead compound among a series of pyrrole derivatives with good in vitro activity against mycobacteria and candidae. Further studies led us to synthesize additional pyrroles bearing the thiomorpholinomethyl moiety and different aryl substituents at N1 and C5. Some of them revealed very active, prompting us to design the new pyrrole derivatives 5-20 in the hope of increasing the activity and better understanding the influence of ortho halogens on the antimycobacterial activity. Microbiological data showed interesting in vitro activity toward Mycobacterium tuberculosis and atypical mycobacteria.     

Ring-substituted quinolines. Part 2: Synthesis and antimycobacterial activities of ring-substituted quinolinecarbohydrazide and ring-substituted quinolinecarboxamide analogues

Additional structural modifications of the new chemical entity, 2,8-dicyclopentyl-4-methylquinoline (DCMQ; MIC = 6.25 μg/mL, M. tuberculosis H37Rv) resulted in the synthesis of four new series of the ring-substituted quinolinecarbohydrazides (series 1–4) constituting 22 analogues. All new derivatives were evaluated for in vitro antimycobacterial activities against drug-sensitive M. tuberculosis H37Rv strain. Certain ring-substituted-2-quinolinecarbohydrazide analogues described herein showed good inhibitory activity. In particular, analogues 4-(1-adamantyl)-2-quinolinecarbohydrazide (2d), 4,5-dicyclopentyl-2-quinolinecarbohydrazide (2e), 4,8-dicyclopentyl-2-quinolinecarbohydrazide (2f), and 4,5-dicyclohexyl-2-quinolinecarbohydrazide (2g) have exhibited the MIC value of 6.25 μg/mL. Further investigation of the most suitable lead prototype, 4-(1-adamantyl)-2-quinolinecarbohydrazide (2d, series 1) led to the synthesis of N2-alkyl/N2,N2-dialkyl/N2-aryl-4-(1-adamantyl)-2-quinolinecarboxamides (series 5) consisting of 13 analogues. Some of the synthesized carboxamides 7a, 7h, and 7m reported herein have exhibited excellent antimycobacterial activities in the range of 6.25–3.125 μg/mL against drug-sensitive and drug-resistant M. tuberculosis H37Rv strains.