Synthesis and evaluation of in vitro antimycobacterial activity of novel 1H-benzo[d]imidazole derivatives and analogues

• We synthesized a new series of benzimidazoles.
• Compounds were tested against M. tuberculosis and M. bovis in vitro.
• Some compounds exhibited excellent tuberculostatic activity.
• Cytotoxic activity towards eukaryotic cells was determined.
• Two derivatives were characterized by high therapeutic index in vitro.

A series of novel 1H-benzo[d]imidazole derivatives and analogues (1–25) have been synthesized and evaluated for tuberculostatic activity. Benzimidazoles substituted at the C-2 position with cyclohexylethyl, cyclohexylpropyl and phenylpropyl moiety or 4-phenylpyridine system were obtained. Compounds 3, 4, 6 and 7 bearing halogen atoms or methyl groups at the benzimidazole system and cyclohexylethyl substituent at the C-2 position showed an excellent tuberculostatic activity against Mycobacterium tuberculosis and Mycobacterium bovis strains with MIC values ranging from 0.75 to 1.5 μg/mL. More importantly, derivatives 4 (5-Bromo-2-(2-cyclohexylethyl)-1H-benzo[d]imidazole) and 6 (2-(2-cyclohexylethyl)-5,6-dimethyl-1H-benzo[d]imidazole) appeared selective for M. tuberculosis and M. bovis as compared with non-malignant eukaryotic cells (LLC-PK1 pig kidney epithelial cell line). These compounds may thus represent a novel, selective class of anti-tubercular agents.

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