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

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 18; p. 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: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.09.2020; Elsevier
• Subjects: Additive effect; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallographic structure; Dipeptidyl nitrile derivatives; Enzymatic inhibitors; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; SAR; Science & Technology; Crystallographic structure; Dipeptidyl nitrile derivatives; Additive effect; Enzymatic inhibitors; SAR; CRUZAIN; CATHEPSIN-K; SUBSITE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127439

[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 < 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.