Synthesis of 2-Vinyl Heterocycles as Potential Electrophilic Components for Inhibitors of Cruzain and NMR Spectroscopic Analysis of Their Thia-Michael Reactions with Thiols
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Cruzain is an essential cysteine protease in Trypanosoma cruzi (T. cruzi), the causative agent of Chagas’ disease. Cruzain is an ideal target for development of potential trypanocidal drugs because of its critical role in the survival of T. cruzi in infected human hosts.Crystallographic analysis of cruzain treated with the covalent inactivator K11777, a peptidomimetic compound with an electrophilic vinyl sulfone substituent, undergoes the formation of a stable C-S bond between cruzain and the vinyl group of the inactivator. We seek to develop new cruzain inactivators in which the vinyl-sulfone group is replaced by isoelectronic vinyl--heterocycle groups which may provide reversible covalent inactivation of cruzain, which would be less subject to selectivity and toxicity problems that plague irreversible inactivators. This report examines the potential of 2-vinyl heterocycles as inhibitors for cruzain by NMR analysis of the thia-Michael addition to the vinyl bond using β-mercaptoethanol (BME), cysteamine (MEA) and L-glutathione (GSH) as Michael donors.
Luna Robles, Mireya (2017). Synthesis of 2-Vinyl Heterocycles as Potential Electrophilic Components for Inhibitors of Cruzain and NMR Spectroscopic Analysis of Their Thia-Michael Reactions with Thiols. Undergraduate Research Scholars Program. Available electronically from