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.