Optimization of azoles as anti-human immunodeficiency virus agents guided by free-energy calculations

Abstract

Efficient optimization of an inactive 2-anilinyl-5-benzyloxadiazole core has been guided by free energy perturbation (FEP) calculations to provide potent non-nucleoside inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (NNRTIs). An FEP "chlorine scan" was performed to identify the most promising sites for substitution of aryl hydrogens. This yielded NNRTIs 8 and 10 with activities (EC50) of 820 and 310 nM for protection of human T-cells from infection by wild-type HIV-1. FEP calculations for additional substituent modifications and change of the core heterocycle readily led to oxazoles 28 and 29, which were confirmed as highly potent anti-HIV agents with activities in the 10-20 nM range. The designed compounds were also monitored for possession of desirable pharmacological properties by use of additional computational tools. Overall, the trends predicted by the FEP calculations were well borne out by the assay results. FEP-guided lead optimization is confirmed as a valuable tool for molecular design including drug discovery; chlorine scans are particularly attractive since they are both straightforward to perform and highly informative.

Figure 1

Some key residues in the NNRTI binding site with the core 2 bound, as created by BOMB and optimized by MCPRO. The full model contains ca. 175 protein residues and the ligand.

Figure 2

Image constructed from the last configuration of an MC/FEP calculation for 29 bound to HIV-RT. Carbon atoms of 29 are in yellow. Fragments of some residues in the binding site are shown along with one of the 1250 water molecules that were included.

Scheme 1

Synthesis of 1,3,4-oxadiazole-2-amines

Scheme 2

Alternative preparation of 1,3,4-Oxadiazole-2-amines

Scheme 3

Synthesis of 1,3,4-Oxadiazole-2,5-diamines

Scheme 4

Synthesis of 2,5-oxazole Derivatives

Scheme 5

Thiazole- and Pyrimidine-Containing NNRTIs³