3‐Aryl‐substituted imidazo[1,2‐a]pyridines as antituberculosis agents

Abstract

Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3‐aryl‐substituted imidazo[1,2‐a]pyridines as potent antituberculosis agents. A small library of 3‐aryl‐substituted imidazo[1,2‐a]pyridines was synthesized using direct arylation, followed by nitro reduction and finally Pd‐catalyzed C−N coupling reactions. The compounds thus obtained were evaluated against Mycobacterium tuberculosis H37Rv. Compound 26 was identified as an antituberculosis lead with a minimum inhibitory concentration of 2.3 μg/ml against M. tuberculosis H37Rv. This compound showed a selectivity index of 35. The docking of 26 in the active site of the M. tuberculosis cytochrome bc1 complex cytochrome b subunit (Mtb QcrB) revealed key π–π interactions of compound 26 with the Tyr389 and Trp312 residues of Mtb QcrB.

Recent developments of imidazo[1,2-a]pyridine analogues as antituberculosis agents

“…With an intent to explore other IPs, Karale et al reported a new potent anti-TB agent, 3-arylsubstituted IP, by replacing the extended amide side chain of Q203 with different substituted aryl or heteroaryl rings at the C-3 position. 55,56 Initially they found a hit compound with a trifluromethylphenyl substitution at the C-3 position (MIC 90 , 21.16 μM). Further SAR exploration of the aromatic ring on C-3, led to amine-substituted 3-arylimidazo[1,2-a]pyridine analog with promising activity against Mtb.…”

“…3 in the original article). 55 Onajole et al reported IPA analogues containing cyclic aliphatic rings at the amide end and evaluated against DS H37Rv, V4207, MDR KZN494, MDR V2475, XDR R506, and TF274 strains of Mtb. 57 SAR studies revealed that the potency of analogues is dependent on the carbon spacer between amide nitrogen and the cyclic aliphatic ring.…”