The antimycobacterial investigation of azepanobetulin and its amide derivative was performed. Both compounds showed increased in vitro antibacterial activity on the H37Rv MTB strain in aerobic and anaerobic conditions. Basing on differences between MIC and IC50 values a predominant bactericidal effect for amide in contrast to azepanobetulin with a bacteriostatic antibacterial mechanism is defined. Both compounds showed a strong antibacterial effect against resistant MTB strains with amide derivative being slightly more active. Amide derivative also showed a higher antibacterial potency against non-tuberculous mycobacterial strains (M. avium, M. abscessus). Molecular docking studies showed that the inhibition of tuberculosinyl adenosine transferase (Rv3378c) could constitute an antimycobacterial mechanism of action for these triterpenic azepane derivatives. The pharmacokinetic profile was evaluated by ADMET studies and azepanobetulin showing the better results was evaluated by in vivo experiments. This compound has demonstrated a statistically significant antimycobacterial activity compared to control, but inferior to isoniazid. Our findings show that pentacyclic triterpene derivatives holding a seven-membered azepane A-ring are the promising template for the development of new agents with high antibacterial potential against M. tuberculosis H37Rv, non-tuberculous mycobacterial and drug- resistant strains.
Keywords: Azepane; Betulin; In vivo, Tuberculosinyl adenosine transferase (Rv3378c); Lupane; M. tuberculosis; Non-tuberculous Resistant MTB strains, ADMET; Triterpenoids.
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