Vinyl Sulfone-Based Peptidomimetics as Anti-Trypanosomal Agents: Design, Synthesis, Biological and Computational Evaluation

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• 作者：Elizabeth Dunny ; William Doherty ; Paul Evans ; J. Paul G. Malthouse ; Derek Nolan ; Andrew J. S. Knox
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6638-6650
• 全文大小：602K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

A series of vinyl sulfone-containing peptidomimetics were rationally designed, synthesized, and evaluated against Trypanosoma brucei brucei. These electrophilic compounds are likely to exert their antitrypanosomal activity via inhibition of trypanosomal cysteine proteases, TbCatB and rhodesain, through alkylation of a key cysteine residue within the protease active site. The series was designed to present complementary groups to naturally recognized peptide substrates while probing tolerance to a range of substitutions at the P1, P1鈥? and P2 positions. The most potent compound, 29 (EC₅₀ = 70 nM, T. b. brucei whole cell assay), displayed minimal toxicity (>785 times selectivity) when assayed for cytotoxicity against the human promyelocytic leukemia (HL-60) cell line. Cells treated with compound 29, as with K777 (2), exhibited an increase in both the number of multinucleated cells and cells with swollen flagellar pockets. Computational analysis revealed a strong correlation between the hypothetical binding mode in TbCatB/rhodesain and trypanocidal activity in vitro.