Synthesis and Evaluation of Oxyguanidine Analogues of the Cysteine Protease Inhibitor WRR-483 against Cruzain

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• 作者：Brian D. Jones ; Anna Tochowicz ; Yinyan Tang ; Michael D. Cameron ; Laura-Isobel McCall ; Ken Hirata ; Jair L. Siqueira-Neto ; Sharon L. Reed ; James H. McKerrow ; William R. Roush
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：7
• 期：1
• 页码：77-82
• 全文大小：372K
• ISSN：1948-5875

文摘

A series of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 were synthesized and evaluated against cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi. Kinetic analyses of these analogues indicated that they have comparable potency to previously prepared vinyl sulfone cruzain inhibitors. Co-crystal structures of the oxyguanidine analogues WRR-666 (4) and WRR-669 (7) bound to cruzain demonstrated different binding interactions with the cysteine protease, depending on the aryl moiety of the P₁′ inhibitor subunit. Specifically, these data demonstrate that WRR-669 is bound noncovalently in the crystal structure. This represents a rare example of noncovalent inhibition of a cysteine protease by a vinyl sulfone inhibitor.