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Phosphonoamidate prodrugs of C5-substituted pyrimidine acyclic nucleosides for antiviral therapy

Pertusati, Fabrizio ORCID:, Serafini, Sara, Albadry, Najmiyah, Snoeck, Robert and Andrei, Graciela 2017. Phosphonoamidate prodrugs of C5-substituted pyrimidine acyclic nucleosides for antiviral therapy. Antiviral Research 143 , pp. 262-268. 10.1016/j.antiviral.2017.04.013

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Acyclic nucleoside phosphonates (ANPs) are nowadays one of the key drugs in the treatment of DNA virus and retrovirus infections. In this work, we report the synthesis and antiviral evaluation of phosphonoamidate and diamidates prodrugs of C5-pyrimidine acyclic nucleosides derivatives functionalized with but-2-enyl- chain. In the phosphonoamidate series, the most active compound 15, showed sub-micromolar activity against varicella zoster virus (VZV) (EC50 =0.09-0.5 μM) and μM activity against human cytomegalovirus (HCMV) and herpes simplex virus (HSV). Separation of single diastereoisomers for compound 14, showed that 14b had better anti-herpesvirus activity and no cytotoxicity compared to the diastereoisomeric mixture 14. Very interestingly, phosphonodiamidate 21 showed anti-herpesvirus activity with excellent activity against wild type and thymidine kinase-deficient (TK-) VZV strains (EC50 = 0.47 and 0.2 μM, respectively) and HCMV (EC50 = 3.5-7.2 μM) without any cytotoxicity (CC50 >100).

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Phosphonoamidate; HCMV; C5-pyrimidine acyclic nucleosides; VZV
Publisher: Elsevier
ISSN: 0166-3542
Date of First Compliant Deposit: 2 May 2017
Date of Acceptance: 24 April 2017
Last Modified: 10 Nov 2023 17:07

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