Trichomoniasis infection is caused by the parasitic protozoan Trichomonas vaginalis. In recent years, resistance to current treatments, such as the 5-nitroimidazole class of antitrichomonal drugs, has drastically increased. For this reason new treatments with novel mechanisms of action are being pursued. Since T. vaginalis is incapable of de novo biosynthesis of nucleobases, salvage pathway enzymes such as nucleoside ribohydrolases (NHs) represent potential therapeutic targets. We previously carried out fragment screens on a purine-specific (AGNH) and pyrimidine-specific (UNH) and identified several classes of ligand-efficient inhibitors. Interestingly, the phenylpyridine scaffold was identified to have activity against both AGNH and UNH. This motif was used as a starting point to synthesize a small array of analogs under palladium catalyzed Suzuki coupling conditions using readily available phenylboronic acids and bromopyridines. The position of the pyridine nitrogen as well as hydroxyl, methyl and nitrile substitutions were varied independently, and then activity was determined using NMR-based activity assays as before. The three compounds shown below represent the best UNH and AGNH inhibitors of the compounds synthesized. The collective SAR suggests divergent vectors for UNH and AGNH. For example, for UNH the substituent on the pyridine must be ortho to the phenol, whereas for AGNH the 2-pyridine must be ortho to the hydroxy group. General SAR trends for both UNH and AGNH suggest that the best inhibition is achieved with phenol substituents. This can be observed when comparing hydroxy substituted phenyl rings to their methoxy substituted counterparts.

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

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.