Deazapurine nucleoside analogues for the treatment of Trichomonas vaginalis

Natto, M. J., Hulpia, F., Kalkman, E. R., Baillie, S., Alhejely, A., Miyamoto, Y., Eckmann, L., Van Calenbergh, S. and de Koning, H. P. (2021) Deazapurine nucleoside analogues for the treatment of Trichomonas vaginalis. ACS Infectious Diseases, 7(6), pp. 1752-1764. (doi: 10.1021/acsinfecdis.1c00075) (PMID:33974405)

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 Trichomonas growth at 10 μM with Z′ 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-T. vaginalis 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 T. vaginalis at a concentrations of just 2 × EC50. 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.

• Item Type: Articles
• Additional Information: We are grateful to the Saudi Ministry of Health for support to MJN. F.H. thanks the Fund for Scientific Research Flanders (FWO) for a postdoctoral fellowship (1226921N). S.V.C. thanks the Hercules Foundation (Project AUGE/17/22 “Pharm-NMR”). This work was supported in part by NIH grant DK120515 (L.E. and Y.M.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Baillie, Mrs Susan and Kalkman, Dr Eric and De Koning, Professor Harry and Alhejely, Amani Saud and Natto, Dr Manal
• Authors: Natto, M. J., Hulpia, F., Kalkman, E. R., Baillie, S., Alhejely, A., Miyamoto, Y., Eckmann, L., Van Calenbergh, S., and de Koning, H. P.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: ACS Infectious Diseases
• Publisher: American Chemical Society
• ISSN: 2373-8227
• ISSN (Online): 2373-8227
• Published Online: 11 May 2021
• Copyright Holders: Copyright © 2021 American Chemical Society
• First Published: First published in ACS Infectious Diseases 7(6): 1752-1764
• Publisher Policy: Reproduced in accordance with the publisher copyright policy