Synthesis and antimycobacterial properties of N-substituted 6-amino-5-cyanopyrazine-2-carboxamides

A series of fifteen new compounds related to pyrazinamide (PZA) were synthesized, characterized with analytical data and screened for antimycobacterial, antifungal and antibacterial activity. The series consists of 6-chloro-5-cyanopyrazine-2-carboxamide and N-substituted 6-amino-5-cyanopyrazine-2-carboxamides, derived from the previous by nucleophilic substitution with various non-aromatic amines (alkylamines, cycloalkylamines, heterocyclic amines). Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis equal to pyrazinamide (12.5-25 μg/mL). More importantly, 6-chloro-5-cyanopyrazine-2-carboxamide and 5-cyano-6-(heptylamino)pyrazine-2-carboxamide were active against Mycobacterium kansasii and Mycobacterium avium, which are unsusceptible to PZA. Basic structure-activity relationships are presented. Only weak antifungal and no antibacterial activity was detected.     

Synthesis and antimycobacterial evaluation of pyrazinamide derivatives with benzylamino substitution

A series of 19 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro whole cell antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two types of Mycobacterium avium. The series consisted of 3-(benzylamino)-5-cyanopyrazine-2-carboxamides and 3-(benzylamino)pyrazine-2,5-dicarbonitriles with various substituents on the phenyl ring. RP-HPLC method was used to determine the lipophilicity of the prepared compounds. Nine compounds exerted similar or better activity against Mycobacterium tuberculosis compared to pyrazinamide (MIC = 6.25–12.5 μg/mL). 3-(Benzylamino)pyrazine-2,5-dicarbonitrile inhibited all of the tested mycobacterial strains with MIC within the range 12.5–25 μg/mL. Although not the most active, 4-NH₂ substituted compounds possessed the lowest in vitro cytotoxicity (hepatotoxicity), leading to selectivity index SI = 5.5 and SI >21.     

New antimycobacterialS-alkylisothiosemicarbazones

In connection with a systematic study of antimycobacterial agents against potentially pathogenic strains the series of 12 S-alkylisothiosemicarbazones was evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, M. fortuitum, two strains of M. intracellulare and three strains of M. avium. Quinoline-4-carbaldehyde-S-hexyl-isothiohydrazone was found to be more active against potentially pathogenic strains than isoniazide.     

In vitro antimycobacterial activities of Physalis angulata L.

The HIV-tuberculosis co-infection has caused an impact on tuberculosis epidemiology all over the world and the efficacies of the therapeutic schemes traditionally prescribed in the treatment of tuberculosis, such as isoniazid, rifampicin and pyrazinamide, have decreased due to the appearance of multidrug-resistant M. tuberculosis strains (MDR). This work is part of research on natural antimicrobial agents from plant extracts through bioassay-guided fractionation, by in vitro determination of the minimum inhibitory concentration (MIC) using the microdilution method with Alamar blue oxidation-reduction dye. Crude CHCl3 Physalis angulata extracts and physalin-containing fractions displayed antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium malmoense and Mycobacterium intracellulare.     

Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2'-'up' fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors

Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2, 4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 2'-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-β-d-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(β-d-arabinofuranosyl)-4-thio-5-hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC(50)=0.5 μg/mL) and M. bovis (MIC(50)=0.5 μg/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC(50)=5.0 μg/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC(50)=1 μg/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC(50)=10 μg/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC(50)>100 μg/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB.     

Antimycobacterial activity of 9-sulfonylated/sulfenylated-6-mercaptopurine derivatives.

A series of 9-sulfonylated/sulfenylated-6-mercaptopurines has been prepared by reaction of 6-mercaptopurine with sulfonyl/sulfenyl halides. These compounds constitute a new class of potent antimycobacterial agents, possessing MIC values against Mycobacterium tuberculosis H37Rv in the range of 0.39-3.39 microg/mL, as well as appreciable activity against Mycobacterium avium. Furthermore, a compound of this small series exhibited good activity (MIC under 1 microg/mL) against several drug resistant strains of M. tuberculosis.     

New antimycobacterial 2,3-dihydro-1-alkylindole-2-thiones

A series of 2,3-dihydroindole-2-thiones was evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, M. fortuitum, two strains of M. intracellulare and three strains of M. avium. 2,3-Dihydro-1-methyl-2-thioxoindole-3-one and 2,3-dihydro-1-butyl-2-thioxoindole-3-one were the most active substances against potentially pathogenic strains, being more active than isoniazide.     

Antimycobacterial activity of piperidinylpropyl esters of alkoxy-substituted phenylcarbamic acids

A series of 17 hydrochlorides of piperidinylpropyl 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 moiety in position 3, were evaluated for in vitro antimycobacterial activity against the strains of Mycobacterium tuberculosis, M. kansasii and M. avium. To describe the structure-antimycobacterial activity relationships (QSAR), an approach based on the Free-Wilson method was employed to express the differences between individual moieties (including propyl and ethyl). The change of ethyl to propyl moiety increases the activity to M. tuberculosis but decreases the antimycobacterial activity to all potentially pathogenic strains under study.     

Synthesis and antimycobacterial activity of 3,5-disubstituted thiadiazine thiones

A series of 3,5-disubstituted thiadiazine thiones (4-24) have been synthesized by reaction of primary amines with carbon disulphide followed by cyclocondensation of the resulting intermediate with formaldehyde and primary amines or amino acids. The compounds were screened for antitubercular activity in vitro against Mycobacterium tuberculosis H37Rv. Three compounds 4, 12 and 18 showed antimycobacterial activity with MIC 12.5 microg/mL. Compound 4, was tested in vitro against five multidrug resistant (MDR) strains of M. tuberculosis and was found to be active. Compound 4 also exhibited activity in vivo. While all the mice died in the untreated group, the mean survival time (MST) of the compound treated mice was enhanced, 33% mice were surviving in treated group and the load of bacilli in the lung was considerably less in the compound treated group than in the untreated control group.     

Antimycobacterial activity: a facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines

A series of twelve dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H(37)Rv and INH resistant M. tuberculosis strains using agar dilution method, four of them showed good activity with MIC of less than 1 μM. Compound 4'-[5-(4-fluorophenyl)pyridin-3-yl]-1'-methyldispiro[indan-2,2' pyrrolidine-3',2″-indan]-1,3,1″-trione (4b) was found to be the most active with MIC of 0.1215 and 5.121 μM, respectively.     

Antimycobacterial activities of 5-alkyl (or halo)-3'-substituted pyrimidine nucleoside analogs

Several 5-alkyl (or halo)-3'-azido (amino or halo) analogs of pyrimidine nucleosides have been synthesized and evaluated against Mycobacterium bovis, Mycobacterium tuberculosis and Mycobacterium avium. Among these compounds, 3'-azido-5-ethyl-2',3'-dideoxyuridine (3) was found to have significant antimycobacterial activities against M. bovis (MIC(50)=1μg/mL), M. tuberculosis (MIC(50)=10μg/mL) and M. avium (MIC(50)=10μg/mL).     

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 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.     

A new group of potential antituberculotics: Hydrochlorides of piperidinylalkyl esters of alkoxy-substituted phenylcarbamic acids

A group of 31 of alkoxy-substituted phenylcarbamic acids with the alkoxy group in ortho, meta or para position, and methyl or ethoxymethyl attached to the ethylene moiety in position 1, including both basic ethyl esters and derivatives branched on ethylene, were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, and M. avium. To describe the structure-antimycobacterial activity relationships (QSARs), an approach based on a combination of the Free-Wilson analysis was used to express the influence of the substituents on the ethylene group as well as the position of the alkoxy groups on the phenyl ring and of the hydrophobicity of alkyls. In vitro antimycobacterial activity becomes higher with increasing hydrophobic properties of the alkoxy groups. The para- and meta-substituted derivatives were more active than the ortho-substituted ones. Substitution of ethylene in position 1 by methyl increased the activity against M. tuberculosis, a similar substitution by ethoxymethyl increased the activity against M. kansasii. The most active compounds were piperidinyl-1-(ethoxymethyl)ethylesters of heptoxyphenylcarbamic acids.     

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.     

Some 3-thioxo/alkylthio-1,2,4-triazoles with a substituted thiourea moiety as possible antimycobacterials.

A series of novel N-alkyl/aryl-N'-[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5-yl)phenyl]thioureas 1-19 and three S-alkylated representatives of the former, N-alkyl/aryl-N'-[4-(3-aralkylthio-4-alkyl/aryl-4H-1,2,4-triazole-5-yl)phenyl]thioureas 20-22, were synthesized and tested for antimycobacterial activity against Mycobacterium tuberculosis H37Rv as well as Mycobacterium fortuitum ATCC 6841 which is a rapid growing opportunistic pathogen. Compounds 4 and 9-11 were found to possess the same MIC value with that of Tobramycin against M. fortuitum ATCC 6841 whereas 1-3 and 21 had positive response against M. tuberculosis H37Rv at varying degrees. Compound 21 was identified as the most potent derivative of the 1-22 series by an MIC value of 6.25 microg/mL and selectivity index of 1.6.     

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.     

Antimycobacterial activity of bisbenzylisoquinoline alkaloids from Tiliacora triandra against multidrug-resistant isolates of Mycobacterium tuberculosis

Bisbenzylisoquinoline alkaloids, tiliacorinine (1), 2'-nortiliacorinine (2), and tiliacorine (3), isolated from the edible plant, Tiliacora triandra, as well as a synthetic derivative, 13'-bromo-tiliacorinine (4), were tested against 59 clinical isolates of multidrug-resistant Mycobacterium tuberculosis (MDR-MTB). The alkaloids 1-4 showed MIC values ranging from 0.7 to 6.2 μg/ml, but they exhibited the MIC value at 3.1 μg/ml against most MDR-MTB isolates. The present work suggests that bisbenzylisoquinoline alkaloids are potential new chemical scaffolds for antimycobacterial activity.     

Antimycobacterial activity: synthesis of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues

In this study, a series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized and evaluated for antimycobacterial activity against Mycobacterium tuberculosis (MTB) H(37)Rv and isoniazid resistant M. tuberculosis (INHR-MTB). All the newly synthesized compounds were showing moderate to high inhibitory activities. The compound 6,7-dimethoxy-3-(4-chloro phenyl)-4H-indeno[1,2-c]isoxazole (4b) was found to be the most promising compound, active against MTB H(37)Rv and INHR-MTB with minimum inhibitory concentrations of 0.22 and 0.34 μM.