Design, Synthesis, Biological Evaluation, and Molecular Modeling Studies of TIBO-Like Cyclic Sulfones as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

TIBO‐ and TBO‐like sulfone derivatives 1 and 2 were designed, synthesized, and tested for their ability to block the replication cycle of HIV‐1 in infected cells. The anti‐HIV‐1 activities of sulfones 3, which were intermediates in the syntheses of 1 and 2, were also evaluated. Surprisingly, the sulfone analogues of TIBO R82913 (compounds 1) were inactive, whereas interesting results were obtained for truncated derivatives 2. Compound 2 w was the most potent among this series in cell‐based assays (EC50=0.07 μM, CC50>200 μM, SI>2857). It was twofold less potent than R82913, but more selective. An X‐ray crystallographic analysis was carried out to establish the absolute configuration of 2 w and its enantiomer 2 x, which were obtained by semipreparative HPLC of 2 v, one of the most potent racemates. Compounds 1–3 were proven to target HIV‐1 RT. In fact, representative derivatives inhibited recombinant HIV‐1 RT in vitro at concentrations similar to those active in cell‐based assays. 3D QSAR studies and docking simulations were developed on TIBO‐ and TBO‐like sulfone derivatives to rationalize their anti‐HIV‐1 potencies and to predict the activity of novel untested sulfone derivatives. Predictive 3D QSAR models were obtained with a receptor‐based alignment by docking of TIBO‐ and TBO‐like derivatives into the NNBS of RT. Sulfone analogues of TIBO that target HIV‐1 reverse transcriptase (RT), are more easily synthesized than the most potent TIBO antivirals. Compounds 1 and 2 were active against HIV‐1 in cell‐based assays, and predictive 3D QSAR models were obtained with a receptor‐based alignment by docking these sulfone derivatives into the non‐nucleoside binding site of RT.