Abstract
A series of acyclic selenopurine nucleosides 3a–f and 4a–g were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir (4a) exhibited the most potent anti-herpes simplex virus (HSV)-1 (EC50 = 1.47 µM) and HSV-2 (EC50 = 6.34 µM) activities without cytotoxicity up to 100 µM, while 2,6-diaminopurine derivatives 4e–g exhibited significant anti-human cytomegalovirus (HCMV) activity, which is slightly more potent than the guanine derivative 4d, indicating that they might act as prodrugs of seleno-ganciclovir (4d).
Highlights
Modified nucleosides have continued to be fruitful resources for the development of antiviral agents [1]
We synthesized the selenium analogues 3 (X = H, R1 = OH, R2 = NH2, seleno-acyclovir) and 4 (X = CH2 OH, R1 = OH, R2 = NH2, seleno-ganciclovir) of 1 and 2 because they are in bioisosteric relationships; we evaluated them for antiviral activity [12]
11 and and 12, 12, which serve as the versatile intermediates for the synthesis of various seleno-acyclovir analogues
Summary
Modified nucleosides have continued to be fruitful resources for the development of antiviral agents [1]. Compound 2 is converted to its monophosphate by viral-encoded kinase (phosphotransferase), which is subsequently converted into the triphosphate by cellular kinase [9]. This triphosphate inhibits HCMV DNA polymerase with a mechanism of action similar to 1 [9]. These drugs 1 and 2 have exhibited drawbacks such as hepatotoxicity [10], poor water solubility, and the appearance of resistant strains [11]. It has been highly desirable to develop new antiviral agents to tackle these problems
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