Synthesis and anti-HIV activity of 5-haloethynyl and 5-(1,2-dihalo)vinyl analogues of AZT and FLT

In this paper, we report the synthesis of hitherto unknown 5-haloethynyl and 5-(1,2-dihalo)vinyluracil nucleoside analogues of the anti-HIV AZT, and FLT drugs. The key step of those syntheses is a Pd(0) cross-coupling at C5 position under Sonogashira conditions. Finally, based on their in vitro anti-HIV activities and their cytotoxicity on PBM, CEM, and VERO cell lines, the best compounds were the 2',3'-dideoxy-3'-fluoro-5-(bromo-2-iodo)vinyluridine (10b, EC₅₀ of 0.6 μM), and the 3'-azido-2',3'-dideoxy-5-(bromo-2-iodo)vinyluridine (16b, EC₅₀ of 1.1 μM).