rifampin and imidazole

The emergence of multidrug resistant strains of Mycobacterium tuberculosis has made tuberculosis more difficult to manage clinically. With the aim of obtaining new and effective anti-mycobacterial agent(s), this study investigated the anti-mycobacterial activity of several imidazole and piperidine derivatives.. Towards obtaining new anti-mycobacterial agents, Mycobacterium smegmatis cells were treated with different compounds for their growth inhibitory activity. Among these, benzyl 1H-imidazole-1-carbodithioate and allyl piperidine-1-carbodiothioate exhibited better inhibition than the others. Thereafter, anti-biofilm property of these two was examined by treating M. smegmatis with these agents before and after the formation of biofilm. The result showed that both the compounds at their sublethal dose inhibited the formation of biofilm as well as dispersed preformed biofilm. Consistently, they augmented the activity of isoniazid or rifampicin against biofilm-encapsulated cells. MTT assay was performed to examine the toxic effects of this combinatorial therapy on different cell lines. Results exhibited a low cytotoxicity for this combinatorial treatment. The activity of these two was also verified against dormant mycobacterial cells and was found to be effective.. The present study identified two compounds that exhibited anti-mycobacterial activities against both planktonic and dormant cells. These two also exhibited anti-biofilm activity at their sublethal dose and augmented the activity of isoniazid and rifampicin against biofilm encapsulated cells.. The current study provides two new agents that have the potential to be used in anti-mycobacterial therapy and may help in public health management.

Topics: Anti-Bacterial Agents; Biofilms; Humans; Imidazoles; Microbial Sensitivity Tests; Mycobacterium smegmatis; Piperidines; Rifampin

In this paper we report the SAR studies of a series of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)amide and N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)sulfonamide derivatives 6(a-o) and 7(a-o), were synthesized in good yields and characterized by (1)H NMR, (13)C NMR and mass spectral analyses. The preparation of the key intermediate highlights an optimized palladium catalyzed (Pd₂(dba)₃/RuPhos) Buchwald cross-coupling of intermediate 2 and 3. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, (Gram-positive), Escherichia coli and Klebsiella pneumoniae (Gram-negative), antifungal activity against Candida albicans, Aspergillus flavus and Rhizopus sp. and antitubercular activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis, Mycobacterium fortuitum and MDR-TB strains. The synthesized compounds displayed interesting antimicrobial activity. The compounds 7d, 7f, 7h and 7n displayed significant activity against Mycobacterium tuberculosis H37Rv strain.

Topics: Amides; Anti-Infective Agents; Antitubercular Agents; Bacteria; Bacterial Infections; Fungi; Humans; Imidazoles; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycoses; Structure-Activity Relationship; Sulfonamides

6,9-Disubstituted purines and 7-deazapurines are known to be powerful inhibitors of Mycobacterium tuberculosis (Mtb) in vitro. Analogs modified in the six-membered ring (imidazopyridines, pyrrolopyridines, benzimidazoles, and indoles) were synthesized and evaluated as Mtb inhibitors. The targets were prepared by functionalization on the bicyclic heterocycle or from simple pyridines. The results reported herein, indicate that the purine N-1, but not N-3, is important for binding to the unknown target. The 3-deazapurines appears to be slightly more active compared to the parent purines and slightly less active than their 7-deazapurine isomers. Removal of both the purine N-3 and N-7 did not result in further enhanced antimycobacterial activity but the toxicity towards mammalian cells was increased. Both 3-deaza and 3,7-dideazapurines exhibited a modest activity against of the Mtb isolate in the state of non-replicating persistence.

Topics: Animals; Antitubercular Agents; Benzimidazoles; Chlorocebus aethiops; Imidazoles; Indoles; Mycobacterium tuberculosis; Purines; Pyridines; Vero Cells

Purine analogs modified in the five-membered ring have been synthesized and examined for antibacterial activity against Mycobacterium tuberculosis H(37)Rv in vitro employing the microplate alamar blue assay (MABA). The 9-deaza analogs were only found to be weak inhibitors, but the 8-aza-, 7-deaza- and 8-aza-7-deazapurine analogs studied displayed excellent antimycobacterial activities, some even substantially better than the parent purine. In the 7-deazapurine series, MIC values between 0.08 and 0.35 μM, values comparable or better than the reference drugs used in the study (MIC rifampicin 0.09 μM, MIC isoniazid 0.28 μM and MIC PA-824 0.44 μM). The five most active compounds were also examined against a panel of drug-resistant Mtb strain, and they all retained their activity. The compounds examined were significantly less active against M. tuberculosis in a state of non-replicating persistence (NRP). MIC in the low-oxygen-recovery assay (LORA) ≥ 60 μM. The 7-deazapurines were somewhat more toxic towards mammalian cells, but still the selectivity indexes were excellent. The non-purine analogs exhibit a selective antimycobacterial activity. They were essentially inactive against Staphylococcus aureus and Escherichia coli.

Topics: Animals; Anti-Bacterial Agents; Chlorocebus aethiops; Drug Resistance, Bacterial; Imidazoles; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Purines; Vero Cells