Based on the favorable antiviral profiles of 4′-substituted nucleosides, novel 1-(2′-deoxy-2′-fluoro-4′-C-ethynyl-β-D-arabinofuranosyl)-uracil (1a), -thymine (1b), and – cytosine (2) analogues were synthesized. Compounds 1b and 2 exhibited potent anti-HIV-1 activity with IC50 values of 86 and 1.34 nM, respectively, without significant cytotoxicity. Compound 2 was 35-fold more potent than AZT against wild-type virus, and also retained nanomolar antiviral activity against resistant strains, NL4-3(K101E) and RTMDR. Thus, 2 merits further development as a novel NRTI drug
