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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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2020-09, Vol.30 (18), p.127439-127439, Article 127439
Hauptverfasser: Matos, Thiago Kelvin Brito, Batista, Pedro Henrique Jatai, dos Reis Rocho, Fernanda, de Vita, Daniela, Pearce, Nicholas, Kellam, Barrie, Montanari, Carlos Alberto, Leitão, Andrei
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Sprache:eng
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Zusammenfassung:[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