Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB

[Display omitted] 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 stere...

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Published in:Bioorganic & medicinal chemistry letters 2020-09, Vol.30 (18), p.127439-127439, Article 127439
Main Authors: Matos, Thiago Kelvin Brito, Batista, Pedro Henrique Jatai, dos Reis Rocho, Fernanda, de Vita, Daniela, Pearce, Nicholas, Kellam, Barrie, Montanari, Carlos Alberto, Leitão, Andrei
Format: Article
Language:English
Subjects:
Additive effect
Crystallographic structure
Dipeptidyl nitrile derivatives
Enzymatic inhibitors
SAR
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Summary:[Display omitted] 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 
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2020.127439