rifampin and benzimidazole

Owing to the rapid rise in antibiotic resistance, infectious diseases have become serious threat to public health. There is an urgent need to develop new antimicrobial agents with diverse chemical structures and novel mechanisms of action to overcome the resistance. In recent years, Quinazoline-benzimidazole hybrids have emerged as a new class of antimicrobial agents active against S. aureus and M. tuberculosis. In the current study, we designed and synthesized fifteen new Quinazoline-benzimidazole hybrids and evaluated them for their antimicrobial activity against S. aureus ATCC 29213 and M. tuberculosis H37Rv. These studies led to the identification of nine potent antibacterial agents 8a, 8b, 8c, 8d, 8f, 8g, 8h, 8i and 10c with MICs in the range of 4-64 μg/mL. Further, these selected compounds were found to possess potent antibacterial potential against a panel of drug-resistant clinical isolates which include methicillin and vancomycin-resistant S. aureus. The selected compounds were found to be less toxic to Vero cells (CC

Topics: Anti-Bacterial Agents; Benzimidazoles; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Quinazolines; Staphylococcus aureus; Structure-Activity Relationship

This paper reports the synthesis and evaluation of some benzimidazole-acrylonitrile hybrid derivatives for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. Among the derivatives studied, 3b was found to be the most active compound with MIC of 0.78 μg/mL against M. tuberculosis. This is a quite good activity compared with ethambutol (MIC = 1.56 μg/mL). Moreover, 3b showed 2.8 log fold reduction in bacterial count of dormant forms of mycobacterium which is more potent than first line drugs isoniazid, ciprofloxacin, rifampicin and moxifloxacin. Having activities against both active and dormant forms of M. tuberculosis,3b may be a useful candidate for the development of new drugs to treat tuberculosis.

Topics: Acrylonitrile; Anti-Bacterial Agents; Benzimidazoles; Dose-Response Relationship, Drug; Drug Design; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship

Structure based drug design was used to develop a compound library of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles. Three structural analogs, SB-P1G10, SB-P8B2 and SB-P3G2 were selected from this library for advanced study. In vitro studies revealed that SB-P8B2 and SB-P3G2 had sigmoidal kill-curves while in contrast SB-P1G10 showed a narrow zonal susceptibility. The in vitro studies also demonstrated that exposure to SB-P8B2 or SB-P3G2 was bactericidal, while SB-P1G10 treatment never resulted in complete killing. The dose curves for the three compounds against clinical isolates were comparable to their respective dose curves in the laboratory strain of Mycobacterium tuberculosis. SB-P8B2 and SB-P3G2 exhibited antibacterial activity against non-replicating bacilli under low oxygen conditions. SB-P3G2 and SB-P1G10 were assessed in acute short-term animal models of tuberculosis, which showed that SB-P3G2 demonstrated activity against M. tuberculosis. Together, these studies reveal an in vitro-in vivo relationship of the 2,5,6-trisubstituted benzimidazoles that serves as a criterion for advancing this class of cell division inhibitors into more resource intensive in vivo efficacy models such as the long-term murine model of tuberculosis and Pre-IND PK/PD studies. Specifically, these studies are the first demonstration of efficacy and an in vitro-in vivo activity relationship for 2,5,6-trisubstituted benzimidazoles. The in vivo activity presented in this manuscript substantiates this class of cell division inhibitors as having potency and efficacy against M. tuberculosis.

Topics: Animals; Antitubercular Agents; Benzimidazoles; Cell Division; Disease Models, Animal; Drug Combinations; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxygen; Rifampin; Tuberculosis

A series of novel 3-cyclohexylpropanoic acid derivatives and 3-cyclohexylpropanoic acid-derived nitrogen heterocyclic compounds (1-8) have been synthesized and evaluated for tuberculostatic activity. Compounds 1a, 1c, 1e and 1f bearing benzimidazole or benzimidazole-like systems showed the most potent tuberculostatic activity against Mycobacterium tuberculosis strains with MIC values ranging from 1.5 to 12.5μg/mL. More importantly 1a (6-chloro-2-(2-cyclohexylethyl)-4-nitro-1H-benzo[d]imidazole) and 1f (2-(2-cyclohexylethyl)-1H-imidazo[4,5-b]phenazine) appeared selective for M. tuberculosis as compared with eukaryotic cells (human fibroblasts), and other antimicrobial strains. These compounds may thus represent a novel, selective class of antitubercular agents. Additionally compound 1a stimulated type I collagen output by fibroblasts, in vitro.

Topics: Antitubercular Agents; Benzimidazoles; Cell Line; Heterocyclic Compounds; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Propionates

A series of N'-substituted-2-(5-nitrofuran or 5-nitrothiophen-2-yl)-3H-benzo[d]imidazole-5-carbohydrazide derivatives were synthesized and investigated for their abilities to inhibit β-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Selected analogues were screened for their antitubercular activity against sensitive MTB H(37)Rv and multidrug-resistant MDR-MTB strains, and cytotoxic activity against a panel of human tumor cell lines and two nontumourogenic cell lines. Compounds 3a, 5a, f, 6g were the most promising as inhibitors of β-hematin formation, however, their effect as inhibitors of hemoglobin hydrolysis were marginal. The most active compounds to emerge from the in vitro and in vivo murine studies were 3a and 6i, suggesting an antimalarial activity via inhibition of β-hematin formation and are as efficient as chloroquine. The cytotoxic and antitubercular activities of the present compounds were not comparable with those of the standard drugs employed. But, however, compound 5b showed better antitubercular activity compared to rifampin against multidrug-resistant MDR-MTB strains. Compounds 3a, 6i and 5b showed a good safety index.

Topics: Animals; Antimalarials; Antitubercular Agents; Benzimidazoles; Cell Line, Tumor; Drug Resistance, Multiple; Hemin; Hemoglobins; Humans; Hydrazines; Hydrolysis; Mice; Plasmodium