Synthesis and antitubercular evaluation of reduced lipophilic imidazo[1,2-a]pyridine-3-carboxamide derivatives

Abstract

A series of reduced lipophilic N-benzylic imidazo[1,2-a]pyridine carboxamides (IPAs) with various side chains were designed and synthesized as new anti-TB agents in this work. Five derivatives A2, A3, A4, B1 and B9 exhibit excellent in vitro activity (MIC: < 0.035 μM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains, and acceptable PK properties. Compound B1 bearing a cyclohexylmethyl piperazine moiety, the same side chain of PBTZ169, was found to have obviously greater AUC_0-∞ and C_max than Q203 and PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery.

Keywords: Antitubercular agents; Pharmacokinetics; imidazo[1,2-a]pyridine carboxamides; structure−activity relationships.