The potent proton-pump inhibitors omeprazole, pantoprazole, and rabeprazole have been previously identified as μM inhibitors of T. vaginalis uridine nucleoside ribohydrolase (UNH). The compounds provide a starting point to develop novel antitrichomonal agents. As a first step in reengineering the compounds to be nM inhibitors of UNH, structure-activity relationships for fragments of the prazole compounds have been determined. The parent prazole compounds consist essentially of substituted benzimidazole and pyridine rings separated by a methylsulfinyl linker. Substituted benzimidazole and pyridine rings selected to represent the structural space around each of the two halves of the prazole parent compounds were obtained commercially. Fragments were tested for activity using an 19F NMR-based activity assay at concentrations of 500 μM and 1 mM. The fragments were also tested for UNH binding using WaterLOGSY 1H NMR experiments. Eight fragments exhibited weak inhibitory activity while two fragments exhibited stronger inhibitory activity, namely 2-(methylthio)benzimidazole and 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine. Five of the fragments, including both of those with strong inhibitory activity, gave WaterLOGSY signals indicative of binding to UNH. The activity and binding data for 2-(methylthio)benzimidazole is interesting in that it was the only fragment tested that contained a sulfur substituent in the same location as the parent prazole compounds. In order to test the requirement for a sulfur substituent at this position, the compound 1-(1H-benzimidazol-2-yl)-2-phenylethanol was synthesized. This compound replaces the sulfoxide group in the parent compound with an alcohol. This compound was found to be active as an inhibitor, suggesting that the sulfoxide is not required for activity. Oxidation of the alcohol group would essentially replace the sulfoxide group with a ketone and is expected to improve inhibition further. The synthesis strategy used to create the ketone linker will ultimately be utilized to link the substituted benzimidazole and pyridine rings with the best activities.

Structure-activity relationships of prazole fragment inhibitors of T. vaginalis uridine nucleoside ribohydrolase using NMR-based activity and binding assays

249th National Meeting (2015)

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