Synthesis and biological evaluation of C5-(1-substituted-1,2,3-triazol-4-yl)-uridines and their phosphoramidate prodrugs

We report the synthesis of a series of 15 uridine analogues bearing a 1-substituted-1,2,3-triazole at the C 5 position of the uracil moiety, along with the preparation of the corresponding phosphoramidate (ProTide) prodrugs. Key step is the regioselective copper-catalyzed azide–alkyne cycloaddition (CuAAC) under microwave irradiation, followed by conversion to the ProTide-type nucleotide prodrugs by reaction with pentafluorophenyl phosphoramidates s. The newly synthesized compounds were evaluated in vitro for antiviral activity against representative DNA viruses (vaccinia virus and herpes simplex virus type 1) and RNA viruses, including human coronavirus HCoV-OC43, Zika virus, Ross River virus, respiratory syncytial virus, and influenza A virus (H1N1). In addition, anticancer activity was assessed against a panel of human cancer cell lines, encompassing pancreatic, colorectal, hematological, brain, lung, neuroblastoma and mantle cell lymphoma models. Among the tested compounds, derivative 23n exhibited antiviral activity against HCoV-OC43 in HEL-299 cell cultures with an IC 50 value of 6.45 μM. Several analogues ( 23a, 23b, 23c and 23m ) inhibited proliferation of Z138 mantle cell lymphoma cells with IC 50 values in the 4.2-5.4 μM range. Notably, compound 23c also demonstrated activity against Molt-4 and HL60 leukemia cell lines, with IC 50 values of 4.53 μM and 4.84 μM, respectively.