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

ACS Medicinal Chemistry Letters
Brian D JonesW R Roush

Abstract

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.

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Citations

Aug 24, 2018·PLoS Neglected Tropical Diseases·Jair L Siqueira-NetoPhilip J Rosenthal
Aug 12, 2017·Current Medicinal Chemistry·Rafael Pinto VieiraRafaela Salgado Ferreira
Mar 4, 2020·Journal of Medicinal Chemistry·Bala C ChennaThomas D Meek
Jun 8, 2021·RSC Medicinal Chemistry·Vinicius BonattoCarlos A Montanari
Dec 25, 2019·The Journal of Organic Chemistry·Olga A StorozhenkoLeonid G Voskressensky
Aug 29, 2020·Organic Letters·Tonghao Zhu, Jie Wu
Aug 23, 2021·Bioorganic & Medicinal Chemistry·Wagner A S JudiceTiago Rodrigues

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