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Deazapurine nucleoside analogues for the treatment of Trichomonas vaginalis

Manal J. Natto, Fabian Hulpia (UGent) , Eric R. Kalkman, Susan Baillie, Amani Alhejeli, Yukiko Miyamoto, Lars Eckmann, Serge Van Calenbergh (UGent) and Harry P. de Koning
(2021) ACS INFECTIOUS DISEASES. 7(6). p.1752-1764
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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 mu M 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 x 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.
Keywords
Infectious Diseases, Trichomonas vaginalis, nucleoside analog, high-throughput screening, tubercidin, mouse model, PURINE, METRONIDAZOLE, DERIVATIVES, VALIDATION, TUBERCIDIN, MANAGEMENT, INFECTION, ASSAY

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Citation

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MLA
Natto, Manal J., et al. “Deazapurine Nucleoside Analogues for the Treatment of Trichomonas Vaginalis.” ACS INFECTIOUS DISEASES, vol. 7, no. 6, 2021, pp. 1752–64, doi:10.1021/acsinfecdis.1c00075.
APA
Natto, M. J., Hulpia, F., Kalkman, E. R., Baillie, S., Alhejeli, A., Miyamoto, Y., … de Koning, H. P. (2021). Deazapurine nucleoside analogues for the treatment of Trichomonas vaginalis. ACS INFECTIOUS DISEASES, 7(6), 1752–1764. https://doi.org/10.1021/acsinfecdis.1c00075
Chicago author-date
Natto, Manal J., Fabian Hulpia, Eric R. Kalkman, Susan Baillie, Amani Alhejeli, Yukiko Miyamoto, Lars Eckmann, Serge Van Calenbergh, and Harry P. de Koning. 2021. “Deazapurine Nucleoside Analogues for the Treatment of Trichomonas Vaginalis.” ACS INFECTIOUS DISEASES 7 (6): 1752–64. https://doi.org/10.1021/acsinfecdis.1c00075.
Chicago author-date (all authors)
Natto, Manal J., Fabian Hulpia, Eric R. Kalkman, Susan Baillie, Amani Alhejeli, Yukiko Miyamoto, Lars Eckmann, Serge Van Calenbergh, and Harry P. de Koning. 2021. “Deazapurine Nucleoside Analogues for the Treatment of Trichomonas Vaginalis.” ACS INFECTIOUS DISEASES 7 (6): 1752–1764. doi:10.1021/acsinfecdis.1c00075.
Vancouver
1.
Natto MJ, Hulpia F, Kalkman ER, Baillie S, Alhejeli A, Miyamoto Y, et al. Deazapurine nucleoside analogues for the treatment of Trichomonas vaginalis. ACS INFECTIOUS DISEASES. 2021;7(6):1752–64.
IEEE
[1]
M. J. Natto et al., “Deazapurine nucleoside analogues for the treatment of Trichomonas vaginalis,” ACS INFECTIOUS DISEASES, vol. 7, no. 6, pp. 1752–1764, 2021.
@article{8737684,
  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 mu M 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 x 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.}},
  author       = {{Natto, Manal J. and Hulpia, Fabian and Kalkman, Eric R. and Baillie, Susan and Alhejeli, Amani and Miyamoto, Yukiko and Eckmann, Lars and Van Calenbergh, Serge and de Koning, Harry P.}},
  issn         = {{2373-8227}},
  journal      = {{ACS INFECTIOUS DISEASES}},
  keywords     = {{Infectious Diseases,Trichomonas vaginalis,nucleoside analog,high-throughput screening,tubercidin,mouse model,PURINE,METRONIDAZOLE,DERIVATIVES,VALIDATION,TUBERCIDIN,MANAGEMENT,INFECTION,ASSAY}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{1752--1764}},
  title        = {{Deazapurine nucleoside analogues for the treatment of Trichomonas vaginalis}},
  url          = {{http://doi.org/10.1021/acsinfecdis.1c00075}},
  volume       = {{7}},
  year         = {{2021}},
}
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