Synthesis, Biological Evaluation, and Structure鈥揂ctivity Relationships of Potent Noncovalent and Nonpeptidic Cruzain Inhibitors as Anti-Trypanosoma cruzi Agents

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• 作者：Rafaela S. Ferreira ; Marco A. Dessoy ; Ivani Pauli ; Mariana L. Souza ; Renata Krogh ; Ana I. L. Sales ; Glaucius Oliva ; Luiz C. Dias ; Adriano D. Andricopulo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2380-2392
• 全文大小：623K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

The development of cruzain inhibitors has been driven by the urgent need to develop novel and more effective drugs for the treatment of Chagas鈥?disease. Herein, we report the lead optimization of a class of noncovalent cruzain inhibitors, starting from an inhibitor previously cocrystallized with the enzyme (K_i = 0.8 渭M). With the goal of achieving a better understanding of the structure鈥揳ctivity relationships, we have synthesized and evaluated a series of over 40 analogues, leading to the development of a very promising competitive inhibitor (8r, IC₅₀ = 200 nM, K_i = 82 nM). Investigation of the in vitro trypanocidal activity and preliminary cytotoxicity revealed the potential of the most potent cruzain inhibitors in guiding further medicinal chemistry efforts to develop drug candidates for Chagas鈥?disease.