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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 H37Ra 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 forin vitrostudies 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 H37Ra, respectively.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Liu P,Yang Y,Ju Y,Tang Y,Sang Z,Chen L,Yang T,An Q,Zhang T,Luo Y

doi

10.1016/j.bioorg.2018.06.004

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

422-432

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(18)30314-6

journal_volume

80

pub_type

杂志文章

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