Pentacycloundecane derived hydroxy acid peptides: A new class of irreversible non-scissile ether bridged type isoster as potential HIV-1 wild type C-SA protease inhibitors

Novel peptides incorporating the PCU derived hydroxy acid (5-hydroxy-4-oxahexacyclo{[}5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)] dodecane) were synthesized and their activity against the resistance-prone wild type C-South African (C-SA) HIV-protease is reported. The attachment of peptides and peptoids to the PCU derived hydroxy acid resulted in a series of structurally diverse promising HIV-1 protease inhibitors. Amongst the nine novel compounds, 16, 17, 20 and 23 gave IC50 values ranging from 0.6 to 5.0 mu M against the wild type C-SA HIV-1 protease enzyme. Docking studies and molecular dynamic (MD) simulations have been carried out in order to understand the binding mode of the PCU moiety at the active site of the HIV protease enzyme. A conserved hydrogen bonding pattern between the PCU derived hydroxy ether and the active site residues, ASP25/ASP25', was observed in all active compounds. (C) 2011 Elsevier Inc. All rights reserved.