Design, synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis

Abstract In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)- 1H -pyrrole-3-carboxylate was found to display inhibitory effects against H 37 Ra with an MIC value of 77 µM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis , a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated for  in vitro  studies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)- N -((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl- 1H - pyrrolyl)methyl)ethan-1-aminehydrochloride 7d , ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl- 1H -pyrrole-3-carboxylate hydrochloride 13i , ethyl 1-(4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl- 1H -pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 µM against Mtb H 37 Ra, respectively.