The design, synthesis and biological evaluation of pseudosymmetric HIV-1 protease inhibitors featuring sulfoximine functionality as a potential transition state mimic

HIV-1 protease is a valid target for inhibiting human immunodeficiency virus (HIV), which is the etiological agent of AIDS. Ten anti-HIV-1 protease drugs have been approved by the US FDA, and have found applications in highly active antiretroviral therapy (HAART), the primary treatment for AIDS. However, the emergence of drug-resistant protease mutant hampers the efficiency of the therapy and thus inhibitors with new structures or novel mechanism are needed to address the issue.;Our research is focused on finding novel entities as transition state mimic (TSM) which, when incorporated into the HIV-1 protease inhibitor structure, would bind favorably with the enzyme and help to alleviate the resistance issue. Based on their sp3 hybridized character and successful applications in related fields, as well as C2 structural symmetry of the HIV-1 protease, we evaluated sulfur and its derivatives as potential TSMs for pseudosymmetric HIV-1 protease inhibitors, and established sulfoximine as the most potent moiety in our design. Compound (2S, 2' S)-43a was identified and characterized as the most potent inhibitor against the HIV-1 protease.;An asymmetric synthesis was subsequently developed for 43a, featuring a lipase PS catalyzed desymmetrization reaction of prochiral diol molecules. The enzymatic reaction successfully provided enantiomerically enriched intermediates and simplified the construction of the designed stereoisomer. The enantioselectivity and diastereoselectivity of reactions were evaluated. Phase transfer catalysis (PTC) conditions were utilized in the key coupling reaction to construct the C-S bond. Interestingly, such conditions did not cause racemization of beta-bromo amide, even though racemization of beta-bromo ester was observed under the same conditions.;The preliminary structure-activity relationship (SAR) studies on the P2/P2' sites of the sulfoximine-centered inhibitors were conducted. Conformationally and structurally modified analogs of amino indanol were incorporated into sulfoximine-centered inhibitors. It is concluded from biological data that (1S, 2R)-(-)- cis-1-amino-2-indanol is the best P2/P2' substituent in our designed inhibitors. The resulting compound 43a exhibits an IC50 of 2.5 nM against the HIV-1 protease and IC50 of 408 nM against the virus.;This research is the first demonstration of the importance of sulfoximine-centered core structure in designing a promising new class of HIV-1 protease inhibitors. The asymmetric synthesis we developed will allow the design of structurally diversified inhibitors featuring the stereochemically controlled sulfoximine functionality.