7nvp
Trypanothione reductase from Trypanosoma brucei in complex with N-{4-methoxy-3-[(4-methoxyphenyl)sulfamoyl]phenyl}-5-nitrothiophene-2-carboxamideTrypanothione reductase from Trypanosoma brucei in complex with N-{4-methoxy-3-[(4-methoxyphenyl)sulfamoyl]phenyl}-5-nitrothiophene-2-carboxamide
Structural highlights
FunctionPublication Abstract from PubMedLeishmania spp. are responsible for up to 1 million new cases each year. The current therapeutic arsenal against Leishmania is largely inadequate, and there is an urgent need for better drugs. Trypanothione reductase (TR) represents a druggable target since it is essential for the parasite and not shared by the human host. Here, we report the optimization of a novel class of potent and selective LiTR inhibitors realized through a concerted effort involving X-ray crystallography, synthesis, structure-activity relationship (SAR) investigation, molecular modeling, and in vitro phenotypic assays. 5-Nitrothiophene-2-carboxamides 3, 6e, and 8 were among the most potent and selective TR inhibitors identified in this study. 6e and 8 displayed leishmanicidal activity in the low micromolar range coupled to SI > 50. Our studies could pave the way for the use of TR inhibitors not only against leishmaniasis but also against other trypanosomatidae due to the structural similarity of TR enzymes. Optimization of Potent and Specific Trypanothione Reductase Inhibitors: A Structure-Based Drug Discovery Approach.,Battista T, Federico S, Brogi S, Pozzetti L, Khan T, Butini S, Ramunno A, Fiorentino E, Orsini S, Di Muccio T, Fiorillo A, Exertier C, Di Risola D, Colotti G, Gemma S, Ilari A, Campiani G ACS Infect Dis. 2022 Aug 12;8(8):1687-1699. doi: 10.1021/acsinfecdis.2c00325., Epub 2022 Jul 26. PMID:35880849[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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