Exploring the Antimycobacterial Profile of N-Alkyl Imidazoles

Abstract

The emergence of drug-resistant Mycobacterium tuberculosis strains and non-tuberculous mycobacteria (NTM) species such as Mycobacterium abscessus, highlights the urgent need for new chemotypes with broad-spectrum antimycobacterial activity. In this study, a series of 1,2,3-triazole-containing compounds and their analogues were evaluated against slow- and fast- growing mycobacteria. While some triazole derivatives exhibited moderate activity, structurally related imidazole and indole analogues lacking the triazole motif were more effective. Based on these findings, we focused on a series of N-alkyl imidazole derivatives bearing linear alkyl chains or ω-functionalized groups (alcohol or ester). Selected hits, D17, D18, D19 (with octyl, decyl, and cetyl chains, respectively), ester D23, and alcohol D25, were evaluated against M. tuberculosis H37Rv and M. abscessus, and for cytotoxicity in Vero cells. Among the selected hits, compounds D17 and D18 exhibited dual activity against both mycobacterial species and favourable selectivity indices. These findings position N-alkyl imidazoles, particularly D17 and D18, as promising starting points for lead optimization in the development of new antimycobacterial therapeutic agents.