Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis

Journal of Medicinal Chemistry
Arun K GhoshHiroaki Mitsuya

Abstract

The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2' ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2' ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

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Citations

Apr 23, 2020·Future Medicinal Chemistry·Jurica NovakVladimir A Potemkin
Jul 25, 2020·The Journal of Pharmacy and Pharmacology·Yahya I AsiriMohd Z Hassan
Jan 8, 2021·Chemical Reviews·Ashley N MatthewCelia A Schiffer
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Larisa V ZhilitskayaNina O Yarosh
Dec 14, 2018·ACS Infectious Diseases·Gordon J LockbaumCelia A Schiffer

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