Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors. Issue 16 (15th August 2016)

• Record Type: Journal Article
• Authors: Stanton, Richard A.; Lu, Xiao; Detorio, Mervi; Montero, Catherine; Hammond, Emily T.; Ehteshami, Maryam; Domaoal, Robert A.; Nettles, James H.; Feraud, Michel; Schinazi, Raymond F.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 16(2016)
• Page Start: 4101
• Page End: 4105
• Publication Date: 2016-08-15
• Subjects: HIV -- Reverse transcriptase -- NNRTI -- FEP; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.06.065
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 compound8 inhibited RT with submicromolar potency (IC50 = 0.73 μM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50 = 9.2, 3.5 μM) 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 = 0.36 μM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.