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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Brito Matos, Thiago Kelvin [1] ; Jatai Batista, Pedro Henrique [1] ; Rocho, Fernanda dos Reis [1] ; de Vita, Daniela [1] ; Pearce, Nicholas [2] ; Kellam, Barrie [3] ; Montanari, Carlos Alberto [1] ; Leitao, Andrei [1]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo IQSC USP, Med & Biol Chem Grp NEQUIMED, Sao Carlos Inst Chem, Av Trabalhador Sao Carlense 400, BR-13566590 Sao Carlos, SP - Brazil
[2] Univ Nottingham, Sch Chem, Nottingham - England
[3] Univ Nottingham, Sch Pharm, Nottingham - England
Total Affiliations: 3
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry Letters; v. 30, n. 18 SEP 15 2020.
Web of Science Citations: 0
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. (AU)

FAPESP's process: 16/07946-5 - Synthesis and evaluation of trypanocidal activity of potential reversible covalent inhibitors of cruzain enzyme
Grantee:Lorenzo Cianni
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 18/15904-6 - Characterization of cysteine protease inhibitors with antineoplastic activity by in silico and cell-based assays coupled with chemical analyses
Grantee:Andrei Leitão
Support Opportunities: Regular Research Grants
FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support Opportunities: Research Projects - Thematic Grants