Design, synthesis and biological evaluation of novel 1, 2, 3-triazole analogues of Imidazo-[1, 2-a]-pyridine-3-carboxamide against Mycobacterium tuberculosis. (August 2021)

• Record Type: Journal Article
• Authors: Nandikolla, Adinarayana; Srinivasarao, Singireddi; Khetmalis, Yogesh Mahadu; Kumar, Banoth Karan; Murugesan, Sankaranarayanan; Shetye, Gauri; Ma, Rui; Franzblau, Scott G.; Sekhar, Kondapalli Venkata Gowri Chandra
• Is Part Of: Toxicology in vitro. Volume 74(2021)
• Publication Date: 2021-08
• Subjects: Molecular docking -- Imidazopyridines -- Triazoles -- Anti-tubercular -- Microplate alamar blue assay -- Low oxygen recovery assay; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2021.105137
• Languages: English
• ISSNs: 0887-2333

Abstract

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 1 HNMR, 13 CNMR, 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. Graphical abstract: Unlabelled Image Highlights: Synthesized and characterized 28 novel 1, 2, 3-triazole-imidazopyridine derivatives In vitro anti-TB activity using MABA & LORA methods against MTB H37Rv was performed. 10b is the most active with MIC 13.74 and 24.63 μg/mL in MABA and LORA methods. In-silico ADMET and docking studies for 10b was carried out and reported.