Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB
Bioorganic & Medicinal Chemistry Letters, 2020•Elsevier
Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve
as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized,
tested against CPB, and analyzed using matched molecular pairs to determine the effects of
stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-
(4-bromophenyl)-2, 2, 2-trifluoroethyl) amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide
(5) was the most potent CPB inhibitor (pKi= 6.82), which was also selective for human …
as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized,
tested against CPB, and analyzed using matched molecular pairs to determine the effects of
stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-
(4-bromophenyl)-2, 2, 2-trifluoroethyl) amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide
(5) was the most potent CPB inhibitor (pKi= 6.82), which was also selective for human …
Abstract
Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized, tested against CPB, and analyzed using matched molecular pairs to determine the effects of stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide (5) was the most potent CPB inhibitor (pKi = 6.82), which was also selective for human cathepsin B (pKi < 5). The inversion of the stereochemistry from S to R was more detrimental to potency when placed at the P2 position than at P3. The p-Br derivatives were more potent than the p-CH3 and p-OCH3 derivatives, probably due to intermolecular interactions with the S3 subsite.
Elsevier
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