Antimycobacterial activities of novel 1-(cyclopropyl/tert-butyl/4-fluorophenyl)-1,4-dihydro- 6-nitro-4-oxo-7-(substituted secondary amino)-1,8-naphthyridine-3-carboxylic acid

Fifty-one 1-(cyclopropyl/tert-butyl/4-fluorophenyl)-1,4-dihydro-6-nitro-4-oxo-7-(substituted secondary amino)-1,8-naphthyridine-3-carboxylic acids were synthesized and evaluated for antimycobacterial in vitro and in vivo 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 synthesized compounds, 1-tert-butyl-1,4-dihydro-7-(4,4-dimethyloxazolidin-3-yl)-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid (10q) was found to be the most active compound in vitro with an MIC of 0.1 microM against MTB and MDR-TB and was 3 and 455 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model 10q decreased the bacterial load in lung and spleen tissues with 2.39 and 3.89-log10protections respectively at the dose of 50 mg/kg body weight.     

Antimycobacterial and phototoxic evaluation of novel 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid

Several newer 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids (10-11a-q) were synthesised from 3,4-difluoro aniline and 3-fluoro-4-nitro aniline by nine-step synthesis. The compounds were evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) as well as being tested for their ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesised compounds, 7-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-nitro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (11l) was found to be the most active compound in vitro, with minimum inhibitory concentrations (MICs) of 0.09 microM and <0.09 microM against MTB and MTR-TB, respectively. Compound 11l was found to be 4 times and >506 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model, 11l decreased the bacterial load in lung and spleen tissues by 30% and 42%, respectively, at a dose of 50 mg/kg body weight.     

Discovery of antimycobacterial spiro-piperidin-4-ones: an atom economic, stereoselective synthesis, and biological intervention

An atom economic and stereoselective synthesis of several spiro-piperidin-4-ones through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin and alpha-amino acids viz . proline, phenylglycine, and sarcosine to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones is described. These compounds were evaluated for their in vitro and in vivo activity against Mycobacterium tuberculosis H37Rv (MTB), multidrug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)). Compound 4-(4-fluorophenyl)-5-phenylpyrrolo(spiro[2.3']oxindole)spiro[3.3']-1'-methyl-5'-(4-fluorophenylmethylidene)piperidin-4'-one (4e) was found to be the most active in vitro with a MIC value of 0.07 microM against MTB and was 5.1 and 67.2 times more potent than isoniazid and ciprofloxacin, respectively. In vivo, compound 4e decreased the bacterial load in lung and spleen tissues with 1.30 and 3.73-log 10 protections respectively and was considered to be promising in reducing bacterial count in lung and spleen tissues.     

Novel antitubercular diallyl/dibenzylthiosemicarbazones endowed with high activity toward multi-drug-resistant tuberculosis

Novel diallyl and dibenzylthiosemicarbazones were prepared by three-step reactions. The compounds were tested for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug-resistant Mycobacterium tuberculosis (MDR-TB). Most of the compounds showed excellent activity toward MDR-TB. Among the thirty compounds (4,5a–o) tested N,N-dibenzyl-2-((5-nitrofuran-2-yl)methylene)hydrazinecarbothioamide (5g) was found to be the most potent compound MICs of 0.55 and 0.12 μM against MTB and MDR-TB.     

Synthesis and in-vitro antimycobacterial activity of amino-5-[(substituted) phenyl]-3-(4-hydroxy-3-methylphenyl)-4,5-dihydro-1H-1-pyrazolylmethanethione

A series of amino-5-[(substituted) phenyl]-3-(4-hydroxy-3-methylphenyl)-4,5-dihydro-1H- 1-pyrazolylmethanethione were synthesized by the reaction between thiosemicarbazide and chalcones and were tested for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv and INH resistant Mycobacterium tuberculosis using bactec method. Among the synthesized compounds, compound (4b), amino-5-(4-chlorophenyl)-3-(4-hydroxy-3-methylphenyl)-4, 5-dihydro-H-1-pyrazolylmethanethione was found to be the most active agent against Mycobacterium tuberculosis H37Rv (MTB) and INH resistant Mycobacterium tuberculosis (INHR-MTB) with minimum inhibitory concentration of 0.43 microM . When compared to INH-compound (4b) was found to be 1.62 fold and 26.41 fold more active against MTB and INHR-MTB, respectively.     

Facile diversity-oriented synthesis and antitubercular evaluation of novel aryl and heteroaryl tethered pyridines and dihydro-6H-quinolin-5-ones derived via variants of the Bohlmann-Rahtz Reaction

The diversity oriented synthesis of substituted pyridines and dihydro-6H-quinolin-5-ones tethered with aryls and heteroaryls was achieved in very good yields through CeCl(3)·7H(2)O-NaI catalyst via variants of the Bohlmann-Rahtz reaction. β-Enaminones derived from various aryl and heteroaryl methyl ketones were regioselectively reacted with ethyl acetoacetate or 5,5-dimethylcyclohexane-1,3-dione or 4,4-dimethylcyclohexane-1,3-dione and ammonium acetate refluxing in 2-propanol. Applicability of nontoxic cerium catalyst, high reactivity with wide range of aryl and heteroaryl β-enaminones leading to diverse analogues, operational simplicity, and shorter reaction time at comparatively low temperatures are prominent features of the developed protocol. These synthesized substituted pyridines and dihydro-6H-quinolin-5-one analogues have been evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) by agar dilution method. Among the 48 compounds screened, six compounds 2-(5-chlorothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 4{13,2}, 2-(5-bromothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 4{14,2}, 2-(5-chloro thiophen-2-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one 4{13,3}, and 2-(5-bromothiophen-2-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one 4{14,3}, 7,7-dimethyl-2-(naphthalen-2-yl)-7,8-dihydroquinoline-5(6H)-one 4{6,2}, 6,6-dimethyl-2-(naphthalen-2-yl)-7,8-di hydroquinolin-5(6H)-one 4{6,3} resulted as the most promising antitubercular agents.     

Novel 1-(4-substituted benzylidene)-4-(1-(substituted methyl)-2,3-dioxoindolin-5-yl)semicarbazide derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) and MDR-TB strain

A series of eighteen new 1-(4-substituted benzylidene)-4-(1-(substituted methyl)-2,3-dioxoindolin-5-yl)semicarbazide derivatives were designed, synthesized and characterized by spectral and elemental analyses. The derivatives were screened in vitro for antimicrobial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) and MDR-TB strains. The activity was expressed as the minimum inhibitory concentration in μg/mL. Among the tested compounds 7j, 7m, 7o and 7q possesses equipotent activity as standard drug Isoniazid against MTB while 7m and 7q exhibited higher activity against MDR-TB strain when compared with both the reference drugs isoniazid and rifampicin. Basic structure activity relationships are presented.     

Synthesis and antimycobacterial activity of some 4H-1,2,4-triazin-5-one derivatives

6-[(Arylmethylenamino)carbonyl]-3-(pyridin-2-yl)-4H-1,2,4-triazin-5-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Some compounds showed interesting activity against a strain of Mycobacterium tuberculosis.     

Synthesis and antituberculosis activity of new N-phenyl-N'-[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-yl)phenyl]thioureas

In this study, eight original N-phenyl-N'-[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-yl)phenyl]thiourea derivatives were synthesized and tested for antituberculosis activity. Antituberculosis activities of the synthesized compounds were screened in vitro using BACTEC 460 Radiometric System against Mycobacterium tuberculosis H37Rv at 6.25 microg/ml. The highest inhibition observed with the synthesized compounds is 67% for N-phenyl-N'-[4-(5-cyclohexylamino-1,3,4-thiadiazole-2-yl)phenyl]thiourea.     

抗结核一线药物及结核分枝杆菌的耐药分子机制

近年来涌现出了耐多药结核病(Multidrug-resistanttuberculosis,MDR-TB)/广泛耐药结核病(Extensively drug-resistant tuberculosis,XDR-TB)。MDR-TB是指由耐异烟肼和利福平两种或以上抗结核药物的结核分枝杆菌引起的结核病。XDR-TB是指不...     

Synthesis and antituberculosis activity of cycloalkylidenehydrazide and 4-aza-1-thiaspiro[4.5]decan-3-one derivatives of imidazo[2,1-b]thiazole

New N2-cycloalkylidene-(6-phenyl/4-chlorophenylimidazo[2,1-b]thiazol-3-yl) acetic acid hydrazides (2a-h and 3a-b) were synthesized by reacting (6-phenyl/4-chlorophenylimidazo[2,1-b]thiazol-3-yl)acetic acid hydrazides with cyclohexanones or cyclopentanone. Furthermore, 2a-h were refluxed with thioglycolic or thiolactic acid to give 4-[[(6-phenyl/4-chlorophenylimidazo[2,1-b]thiazol-3-yl) acetyl]amino]-4-aza-1-thiaspiro[4.5]decan-3-ones (4a-h and 5a-h). The structures of the title compounds were established by spectral data (IR, 1H-NMR, 13C-NMR and EIMS (Electron Impact Mass Spectrometry)) and elemental analysis. The synthesized compounds were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). The compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at a concentration of 6.25 micrograms/ml against M. tuberculosis H37Rv (ATCC 27294) in Bactec 12B medium using the Bactec 460 radiometric system or a broth microdilution assay, the Microplate Alamar Blue Assay (MABA). Compounds 2f, 2h, 3b, 4a, 4c, 4d, 5a-e and 5h demonstrating at 1-east 90% inhibition in the primary screen were re-tested at lower concentrations against M. tuberculosis H37Rv (ATCC 27294) to determine the actual minimum inhibitory concentration (MIC) using MABA. The most active compounds were found to be 4d and 5c. The structure-activity relationships of the derivatives were investigated.     

Synthesis and antimycobacterial activity of 5-aryl-1-isonicotinoyl-3-(pyridin-2-yl)-4, 5-dihydro-1H-pyrazole derivatives

5-Aryl-1-isonicotinoyl-3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazole derivatives were synthesized and tested for their in vitro antimycobacterial activity. The compounds showed an interesting activity against a strain of Mycobacterium tuberculosis and a human strain of M. tuberculosis H4.     

Synthesis and biological activity of 5-alkyl-6-(alkylsulfanyl)- or 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides and corresponding thioamides

Nucleophilic substitution of chlorine in 5-alkyl-6-chloropyrazine-2-carboxamides with various alkyl and arylthiolates afforded 20 5-alkyl-6-(alkylsulfanyl)- and 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides. The reaction of the amides with Lawesson's reagent yielded the corresponding thioamides. The assessment of in vitro antimycobacterial and antifungal activity of the compounds was carried out. In both series, the antimycobacterial activity increases with increasing molecular weight of the alkylsulfanyl group in position 6 of the pyrazine ring. Thioamides exhibited higher activity than the corresponding amides. 5-Butyl-6-(phenylsulfanyl)pyrazine-2-carbothioamide (2j) possessed the highest activity (91% inhibition) against Mycobacterium tuberculosis and also the highest lipophilicity (log P = 4.95). Only a poor in vitro antifungal effect was noted in 5-butyl-6-(butylsulfanyl)pyrazine-2-carboxamide (1i) and 6-(ethylsulfanyl)-5-isobutylpyrazine-2-carbothioamide (2q) against Trichophyton mentagrophytes and Absidia corymbifera.     

Antimycobacterial activity of 5-arylidene aromatic derivatives of hydantoin

Various 5-(chlorobenzylidene)-2-isoniazido and 5-(chlorobenzylidene)-2-amino substituted derivatives of imidazoline-4-one were synthesized and evaluated in the primary assay for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Eight of them exhibited > 90% inhibition in the primary screening at 12.5 microg/ml. For these primarily selected compounds the actual MIC and IC50 values were determined. Two of the isoniazid derivatives, for which MIC < 3.13 microg/ml and SI > 10, were selected for further screening and investigated for efficacy in vitro in a TB-infected macrophage model. The most promising compound, 5-(3-chlorobenzylidene)-2-(isonicotinoylhydrazino)-imidazoline-4-one, with activity in vitro comparable with rifampin (MIC = 0.8 microg/ml. SI > 78) was tested in vivo in the animal tuberculosis model but exhibited insignificant activity. For several compounds the primary screening of antimycobacterial activity against Mycobacterium avium (ATCC 25291) was conducted as well, but none of them demonstrated satisfactory activity.     

Synthesis,characterization and evaluation of antituberculosis activity of some hydrazones

Several new hydrazone derivatives were prepared by the reaction of some active hydrogen compounds with the diazonium salts of 4-amino-3,5-di/1,3,5-trimethylpyrazoles at 0-5 degrees C. Structures of the new substances were confirmed using UV, IR, 1H NMR, 13C NMR and EI-mass spectral data. In vitro antituberculosis activity of these compounds were tested on Mycobacterium tuberculosis H37Rv at 6.25 microg/ml. Both hydrazone products, ethyl 2-[(3,5-dimethylpyrazole-4-yl)hydrazono]-3-oxobutyrate (3d) and methyl 2-[(3,5-dimethylpyrazole-4-yl)hydrazono]4-methoxy-3-oxobutyrate (3e) showed 29 and 28% inhibition against M. tuberculosis, respectively.     

Synthesis and in‐vitro Antimycobacterial Evaluation of 1‐(Cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐ 8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids

Fifty one newer 1‐(cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids were synthesized from 1,3‐dichloro‐2‐methylbenzene and evaluated for in‐vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi‐drug resistant Mycobacterium tuberculosis (MDR‐TB), and Mycobacterium smegmatis (MC²). Among the synthesized compounds, 1‐cyclopropyl‐1,4‐dihydro‐7‐(3,4‐dihydro‐6,7‐dimethoxyisoquinolin‐2(1H)‐yl)‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9p was found to be the most active compound in vitro with a MIC value of 0.39 μM against MTB. Against MDR‐TB, compound 7‐(2‐carboxy‐5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl)‐1‐cyclopropyl‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9n was found to be the most active with a MIC value of 0.09 μM.     

Inhibition of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium by novel dideoxy nucleosides

The prevalence of tuberculosis (TB) and mutidrug-resistant tuberculosis (MDR-TB) has been increasing, leading to serious infections, high mortality, and a global health threat. Here, we report the identification of a novel class of dideoxy nucleosides as potent and selective inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis, and drug-resistant Mycobacterium tuberculosis. A series of 5-acetylenic derivatives of 2',3'-dideoxyuridine (3-8) and 3'-fluoro-2',3'-dideoxyuridine (22-27) were synthesized and tested for their antimycobacterial activity against M. bovis, M. tuberculosis, and M. avium. 2',3'-Dideoxyuridine possessing 5-decynyl, 5-dodecynyl, 5-tridecynyl, and 5-tetradecynyl substituents (4-7) exhibited the highest antimycobacterial activity against all three mycobacteria. In contrast, in the 3'-fluoro-2',3'-dideoxyuridine series, a 5-tetradecynyl analogue (26) displayed the most potent activity against these mycobacteria. Among other derivatives, 5-bromo-2',3'-dideoxycytidine (11), 5-methyl-2',3'-dideoxycytidine (12), and 5-chloro-4-thio-2',3'-dideoxyuridine (19) exhibited modest inhibition of M. bovis and M. tuberculosis. In the series of dideoxy derivatives of adenosine, guanosine, and purines, 2-amino-6-mercaptoethyl-9-(2,3-dideoxy-beta-d-glyceropentofuranosyl)purine (32) and 2-amino-4-fluoro-7-(2,3-dideoxy-beta-d-glyceropentofuranosyl)pyrrolo[2,3-d]pyrimidine (35) were the most efficacious against M. bovis and M. tuberculosis, and M. avium, respectively.     

Synthesis and antimycobacterial activity of [5-(pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid arylidene-hydrazide derivatives

[5-(Pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid arylidene-hydrazide derivatives were synthesized and tested for their in vitro antimycobacterial activity. Some compounds showed a feable activity against a strain of Mycobacterium tuberculosis and a strain of Mycobacterium avium.     

Increasing resistance of M. tuberculosis to anti-TB drugs in Saudi Arabia

The incidence of drug resistance in Mycobacterium tuberculosis (MTB) isolated from our hospital between April 1996 and March 1998 was compared with an earlier study (1993-1995). Thirty (29.7%) of 101 MTB isolates were resistant to one or more anti-TB drugs and 21 (20%) of 101 were multi-drug resistant M. tuberculosis (MDR-TB). Resistance was most common to isoniazid (28.7%), followed by streptomycin (22.8%) and rifampicin (20.8%). Resistance to pyrazinamide and ethambutol was 7.9 and 6.9%, respectively. There was a three-fold increase in resistance compared with the earlier study.