Discovery of potent HIV-1 protease inhibitors incorporating sulfoximine functionality

Based on the unique property of sulfoximine and the homodimeric C2 structural symmetry of HIV-1 protease, a novel class of sulfoximine-based pseudosymmetric HIV-1 protease inhibitors was designed and synthesized. The sulfoximine moiety was demonstrated to be important for HIV-1 protease inhibitor potency. The most active stereoisomer (2S,2′S) displays a potency of 2.5 nM (IC50) against HIV-1 protease and an anti-HIV-1 activity of 408 nM (IC50). A possible mode of action is proposed.