Design, synthesis and biological evaluation of novel 1,2,3-triazole analogues of Imidazo-[1,2-a]-pyridine-3-carboxamide against Mycobacterium tuberculosis

Abstract

Twenty-eight novel 1,2,3-triazole analogues of imidazo-[1,2-a]-pyridine-3-carboxamide were designed and synthesized based on hybridization approach. The structure of the final compounds are characterized using 1HNMR, 13CNMR, LCMS and elemental analyses and are screened in vitro for anti-tubercular activity using low-oxygen recovery assay (LORA) non-replicating and using microplate alamar blue assay (MABA) against replicating M. tuberculosis. MIC was determined. From the obtained results, it was observed that, among (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)(4-((1-subtituted phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)methanones and (6-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)(4-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)methanones, compounds with substitution at para position with electron electron releasing groups exhibited the best activity (< 34 μg/mL). Amidst, (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)(4-(2-(4-alkyl/substituted aryl-1H-1,2,3-triazol-1-yl)ethyl)piperazin-1-yl)methanones and (6-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)(4-(2-(4- alkyl/substituted aryl -1H-1,2,3-triazol-1-yl)ethyl)piperazin-1-yl)methanones, compounds with long alkyl chain or cyclo propyl group were most active (< 21 μg/mL) in MABA method against the tested strain of MTB. Compound 10b emerged to be the most active compound in MABA and LORA with MIC values 13.74 and 24.63 μg/mL respectively. In-silico ADMET parameters were also predicted for the significantly active compound. Finally, molecular docking study was carried out to predict the feasible binding pattern of the most active compound at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB-4TZK) using Glide module of Schrodinger software.