Design, Synthesis, Protein−Ligand X-ray Structure,and Biological Evaluation of a Series of Novel Macrocyclic Human ImmunodeficiencyVirus-1 Protease Inhibitors to Combat Drug Resistance.

The structure-based design, synthesis, and biological evaluationof a series of nonpeptidic macrocyclic HIV protease inhibitors aredescribed. The inhibitors are designed to effectively fill in thehydrophobic pocket in the S1′−S2′ subsites andretain all major hydrogen bonding interactions with the protein backbonesimilar to darunavir (1)or inhibitor 2.The ring size, the effect of methyl substitution, and unsaturationwithin the macrocyclic ring structure were assessed. In general, cyclicinhibitors were significantly more potent than their acyclic homologues,saturated rings were less active than their unsaturated analoguesand a preference for 10- and 13-membered macrocylic rings was revealed.The addition of methyl substituents resulted in a reduction of potency.Both inhibitors 14band 14cexhibited markedenzyme inhibitory and antiviral activity, and they exerted potentactivity against multidrug-resistant HIV-1 variants. Protein−ligandX-ray structures of inhibitors 2and 14cprovided critical molecular insights into the ligand-binding siteinteractions. [ABSTRACT FROM AUTHOR]