Deazapurine Nucleoside Analogues for the Treatment of <i>Trichomonas vaginalis</i>

Abstract

Trichomoniasis is the most common nonviral sexually transmitted disease in humans, but treatment options are limited. Here, we report a resorufin-based drug sensitivity assay for high-throughput microplate-based screening under hypoxic conditions. A 5203-compound enamine kinase library and several specialized compound series were tested for the inhibition of <i>Trichomonas</i> growth at 10 μM with <i>Z</i>' values of >0.5. Hits were rescreened in serial dilution to establish an IC₅₀ concentration. A series of 7-substituted 7-deazaadenosine analogues emerged as highly potent anti-<i>T</i>. <i>vaginalis</i> agents, with EC₅₀ values in the low double digit nanomolar range. These analogues exhibited excellent selectivity indices. Follow-up medicinal chemistry efforts identified an optimal ribofuranose and C7 substituent. Several nucleosides rapidly cleared cultures of <i>T</i>. <i>vaginalis</i> at a concentrations of just 2 × EC₅₀. Preliminary <i>in vivo</i> evaluation in a murine trichomoniasis model (<i>Tritrichomonas foetus</i>) revealed promising activity upon topical administration, validating purine nucleoside analogues as a new class of antitrichomonal agents.