Progress towards new conformationally constrained HIV-1 protease inhibitors

Two series of molecules containing a trisubstituted cyclopentyl group as the central unit were synthesized and evaluated as inhibitors of HIV-1 protease (HIV PR). In the first series of molecules (13–20), the central unit A, 3-(N-acyl)amino-2-hydroxy-1-cyclopentylacetyl, was designed so as to reproduce three of the central interactions found in the ‘classical’ complex HIV PR-JG365 inhibitor. Significant inhibitions (IC50 ∼ 10 μM) were obtained with compound 20 in which the central unit was elongated by Z-Ile-Phe at the N-terminus and by Val-OMe at the C-terminus. In the second series of molecules (21–28), the central unit B, 3-hydroxy-2-(N-acyl)amino-1-cyclopentylacetyl, was obtained in the first steps of the synthesis. Unexpectedly better inhibitions were observed with these derivatives (Ki = 2 μM for compound 28). Docking and molecular dynamics simulations performed with compound 28 into HIV PR suggested that the HIV PR-28 complex should have a structure analogous to that of the recently described HIV PR-urea complex.