Trichomoniasis is the most prevalent non-viral sexually transmitted disease that infects an estimated 276 million people worldwide. Trichomoniasis is caused by Trichomonas vaginalis, a flagellated parasitic protozoan. Current 5-nitroimidazole treatments are becoming less effective due to developing resistance by the parasite. For this reason, the advancement of improved treatments with novel mechanisms is crucial. T. vaginalis is incapable of de novo biosynthesis of nucleobases, and therefore its nucleoside ribohydrolases must scavenge them from the host. The uridine nucleoside ribohydrolase enzyme was previously screened against the NIH Clinical Compound Collection as well as a diversity fragment library using 19F NMR spectroscopy to monitor the hydrolysis of 5-fluorouridine. The most common fragment scaffolds identified were acetamides, benzimidazoles, cyclic ureas, pyridines, and pyrrolidines. These fragment scaffolds were used to select available similarity compounds and to synthesize new compounds in order to explore molecular complementarity within the enzyme active site. Collectively, the data defined emerging structure-activity relationships that suggest likely vectors and chemical modifications for improving inhibition potency while maintaining ligand efficiency. The structure-activity relationships suggest that the fragment scaffolds interact primarily with the nucleobase regions of the active site. Thus, larger compounds with substituents that extend into the ribose and Ca2+ binding regions are particularly attractive. The data establishes a platform for ongoing medicinal chemistry development of compounds with nM potency that will provide the tools for in vitro target validation against both 5-nitroimidazole-sensitive and 5-nitroimidazole-resistant T. vaginalis strains.

Structure-activity relationships of fragment-based inhibitors of Trichomonas vaginalis uridine nucleoside ribohydrolase

2019 Spring National Meeting

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