Trichomoniasis is the most prevalent non-viral sexually transmitted diseases. It is caused by the parasitic protozoan Trichomonas vaginalis. Current treatments use 5-nitroimidazoles to damage DNA residues, but due to increasing resistance over time, there is a need for a novel treatment. T. vaginalis is incapable of de novo synthesis of nucleobases and therefore needs to acquire them from the host. T. vaginalis uses salvage pathway enzymes to metabolize the host’s nucleosides, converting them into ribose and the corresponding nucleobase. Two enzymes involved in this salvage pathway are Uridine Nucleoside Ribohydrolase (UNH) and Adenosine-Guanosine Nucleoside Ribohydrolase (AGNH). Screening of a fragment diversity library against both UNH and AGNH resulted in multiple classes of compounds with IC50 values of ~100 μM. Multiple hits from the fragment screen were biaryl compounds, with phenyl pyridine and phenyl pyrazole as two common ones. Using Suzuki coupling we were able to synthesize a variety of analogs and test them against UNH and AGNH. We will report the synthesis and biological activity of these biaryl compounds on UNH and AGNH.

Synthesis and evaluation of biaryl compounds as inhibitors of nucleoside hydrolases to treat trichomoniasis

ACS Fall 2021

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