Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors

Abstract

A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index >100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50=0.73μM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50=9.2, 3.5μM) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50=0.36μM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.

Keywords: FEP; HIV; NNRTI; Reverse transcriptase.

Figure 1.

7-Azaindole core has six available positions for substitutions.

Figure 2.

Ten most potent 7-azaindoles arranged by molecular mass.

Figure 3.

8 (a) and 9 (b) docked into the NNRTI-binding pocket of PDB ID: 2B6A and 10 (c) in 3IS9. Residues found to mutate after treatment with 8 (V108I) and 9 (E138K) are highlighted in their respective images.

Scheme 1.

Reagents and conditions: (a) Ar, M.S. (3 Å), MeOH reflux 4–6 h, 42–48%; (b) DDQ, DCM, rt, 1–2 h, 50–85%.