Thiosulfonate-Based Targeted Covalent Cruzipain Inhibitors with Enhanced Bioactivity Translation for Antichagasic Therapy.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-02-24 eCollection Date: 2025-03-13 DOI:10.1021/acsmedchemlett.4c00631

Juan Pablo Cerutti, Lucas Abreu Diniz, Viviane Corrêa Santos, Salomé Catalina Vilchez Larrea, Guillermo Daniel Alonso, Rafaela Salgado Ferreira, Wim Dehaen, Mario Alfredo Quevedo

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引用次数: 0

Abstract

Chagas disease remains a neglected tropical disease with limited therapeutic options and a pressing need for new antichagasic agents. In this context, Cruzipain (CZP), the main cysteine protease of T. cruzi, has been validated as a promising target for reversible targeted covalent inhibitors (TCIs). Building upon our previous research, this study reports phenyl thiosulfonate (TSO)-based TCIs, designed to optimize enzymatic performance and enhance bioactivity translation from in vitro CZP inhibition to T. cruzi-infected cell models. Among ten potent phenyl TSO TCIs, TSO-13 exhibited high CZP inhibitory potency, selectivity over human cathepsin L, and excellent bioactivity translation in parasite-infected cells. Computational studies highlighted the dual benefit of the TSO moiety in combining optimal reactivity with enhanced encounter complexes' stability. Overall, these findings position triazole-based phenyl TSO derivatives as promising candidates for rational CZP inhibitor design, representing a valuable contribution for developing innovative antichagasic agents.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.