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Identification of benzofurano[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors

2013; Elsevier BV; Volume: 23; Issue: 9 Linguagem: Inglês

10.1016/j.bmcl.2013.02.042

1464-3405

Martin Tremblay, Richard C. Bethell, Michael G. Cordingley, Patrick DeRoy, Jianmin Duan, Martin Duplessis, Paul Edwards, Anne‐Marie Faucher, Ted Halmos, Clint A. James, Cyrille Kuhn, Jean‐Eric Lacoste, Louie Lamorte, Steven R. LaPlante, Éric Malenfant, Joannie Minville, Louis Morency, Sébastien Morin, Daniel Rajotte, Patrick Salois, Bruno Simoneau, Sonia Tremblay, Claudio F. Sturino,

Pneumocystis jirovecii pneumonia detection and treatment

Screening of our sample collection led to the identification of a set of benzofurano[3,2-d]pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI). Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold. The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency. Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors.