Open AccessDeazapurine Nucleoside Analogues for the Treatment of Trichomonas vaginalis
Author(s) -
Manal J. Natto,
Fabian Hulpia,
Eric R. Kalkman,
Susan Baillie,
Amani Alhejeli,
Yukiko Miyamoto,
Lars Eckmann,
Serge Van Calenbergh,
Harry P. de Koning
Publication year - 2021
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.1c00075
Subject(s) - trichomonas vaginalis , nucleoside , medicine , trichomonas vaginitis , trichomonas , biology , virology , gynecology , genetics
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 Trichomonas growth at 10 μM with Z ' values of >0.5. Hits were rescreened in serial dilution to establish an IC 50 concentration. A series of 7-substituted 7-deazaadenosine analogues emerged as highly potent anti- T . vaginalis agents, with EC 50 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 T . vaginalis at a concentrations of just 2 × EC 50 . Preliminary in vivo evaluation in a murine trichomoniasis model ( Tritrichomonas foetus ) revealed promising activity upon topical administration, validating purine nucleoside analogues as a new class of antitrichomonal agents.