Trichomoniasis is the most prevalent, non-viral sexually transmitted disease. It is caused by the parasitic protozoan Trichomonas vaginalis. The parasite has shown increasing resistance to the current 5-nitroimidazole therapies indicating the need for new therapies with different mechanisms. T. vaginalis is an obligate parasite in that it is incapable of the de novo synthesis of purine and pyrimidine rings. It must scavenge nucleosides from host cells and then use salvage pathway enzymes to obtain the nucleobases. The first step in this pathway is the hydrolysis of nucleosides to release the nucleobases. The uridine nucleoside ribohydrolase enzyme was screened against a 2,000-compound diversity subset of the AstraZeneca fragment library using an 19F NMR-based activity assay to monitor the reaction using 5-fluorouridine as the substrate. Six series of inhibitors with emerging SAR were identified including scaffolds based on acetamides, cyclic ureas or ureas, pyridines, and pyridones. A number of potent singleton compounds were identified as well. Included among the active fragments were 11 compounds with IC50 values ~ 10 μM, eight of which have ligand efficiency values of 0.5 or better. The chemical templates identified differ substantially from 5-nitroimidazoles. They are presently serving as the basis for medicinal chemistry efforts aimed at discovering compounds with nM potency that can be tested in vitro for target validation against both 5-nitroimidazole-sensitive and 5-nitroimidazole-resistant T. vaginalis strains.

Identification of ligand-efficient inhibitors of Trichomonas vaginalis uridine nucleoside ribohydrolase using NMR-based fragment screening

255th National Meeting (2018)

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