Synthesis, antiviral evaluation, molecular docking study and cytotoxicity of 5 ′-phosphorylated 1,2,3-triazolyl nucleoside analogues with thymine and 6-methyl uracil moieties

AbstractA comparative analysis of in vitro antiviral activity (in terms of the concentration of semi-maximal inhibition, IC50) against influenza virus A/PR/8/34 (H1N1) of a large series of parent 1,2,3-triazolyl nucleoside analogues (with uracil, thymine, 6-methyluracil, quinazoline-2,4-dione moieties as nucleic bases) and their prodrug forms with masked 5 ʹ-phosphate groups (diethyl phosphate, diphenyl phosphate, phosphoramidate) and negatively chargedH-phosphonate and monophosphate groups was carried out. Obtained structure-activity relationships were interpreted based on the assumption that the synthesized parent 1,2,3-triazolyl nucleoside analogues and their prodrug forms, by analogy with the literature data, are metabolized by cellular kinases to their active 5 ʹ-triphosphate forms that inhibit the activity of viral RNA-dependent RNA polymerase (RdRp). A correlation was found between the experimental values of IC50 and the theoretical values of the binding energies of 5 ʹ-triphosphate derivatives of the parent 1,2,3-triazolyl nucleoside analogues in the active site of RdRp.Graphical Abstract
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research