A SERIES OF PENICILLIN DERIVED C2-SYMMETRICAL INHIBITORS OF HIV-1 PROTEINASE - SYNTHESIS, MODE OF INTERACTION, AND STRUCTURE-ACTIVITY-RELATIONSHIPS

The C2-symmetric diester 1 was identified by random screening as a nov el inhibitor of HIV-1 proteinase. This led to the preparation of a ser ies of related more potent amides from readily accessible penicillins. Many of the compounds showed potent antivirial activity in HIV-1-infe cted MT-4 cells and an ability to inhibit syncytia formation in infect ed C8166 cells, with no evidence of cytotoxicity. The compounds showed no activity against other aspartyl proteinases (renin, pepsin, and ca thepsin D). Structure-activity relationships support a symmetrical int eraction with the enzyme. Pharmacokinetic evaluation of the ethylamide 3 revealed it was subject to rapid plasma clearance and had low oral bioavailability.