Synthesis of 3"-substituted TSAO derivatives with anti-HIV-1 and anti-HIV-2 activity through an efficient palladium-catalyzed cross-coupling approach

Various synthetic studies for the introduction of several functional groups at position 3" of the spiro moiety of TSAO derivatives have been explored. Among, them, Stille cross-coupling of 3"-iodo-TSAO derivatives with different stannanes provided an efficient and straightforward route for the direct and selective functionalization of the 3"-position of the sultone spiro moiety via carbon-carbon bond formation. The compounds synthesized were evaluated for their inhibitory effect on HIV-1 and HIV-2 replication in cell culture. The introduction of a bromine and particularly an iodine at the 3"-position conferred the highest anti-HIV-1 activity. In contrast, the presence at this position of (un)substituted vinyl, alkynyl, phenyl, or thienyl groups markedly diminished the anti-HIV-1 activity. Surprisingly, several of the 3"-alkenyl-substituted TSAO derivatives also gained anti-HIV-2 activity at subtoxic concentrations, an observation that is very unusual for NNRTIs and never observed before for TSAO derivatives. Finally, the anti-HIV-1 activity of some of the 3"-substituted TSAO derivatives is discussed in light of our recently proposed molecular model of interaction of TSAO derivatives with the interphase between the two subunits of HIV-1 reverse transcriptase.