Structure-based design of achiral anthranilamides as P2/P2′ surrogates for symmetry-based HIV protease inhibitors: design, synthesis, X-ray structure, enzyme inhibition and antiviral activity

Guided by the structure of HIV PR complexed with 2S,3R,4S,5S-2,5-bis[N,Nʹ-((3-hydroxy-2-methylphenyl)carbonyl)amino]-3,4-dihydroxy-1,6-diphenyl hexane (1), a novel, achiral, non-peptidic anthranil (Ant) group was designed as a P2/P2′ ligand. Symmetry-based inhibitors containing N-(2-pyridinylmethoxy-carbonyl)anthranil group are potent anti viral agents. Compounds 12 and 14 exhibited protease inhibitory activity of 60 and 70 pM, anti viral activity of 13 and 56 nM and cellular toxicity of> 10 uM respectively. Abstract We describe a HIV PR/1 structure-guided design of the novel, nonpeptidic, achiral anthranilamide group as a P2/P2′ ligand for the symmetry-based HIV PR inhibitors. X-ray crystallographic analysis of HIV PR/12 complex reveal that the anthranilamide group participates in both the polar and hydrophobic interactions that are commonly observed between the enzyme and peptidic inhibitor in the vicinity of the S2/S2′ subsites. The antiviral activity of compound 12 compares favorably with other potent HIV PR inhibitors currently undergoing clinical trials