Ghosh_2018_J.Med.Chem_61_4561

Reference

Title : 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 - Ghosh_2018_J.Med.Chem_61_4561
Author(s) : Ghosh AK , P RN , Kovela S , Rao KV , Brindisi M , Osswald HL , Amano M , Aoki M , Agniswamy J , Wang YF , Weber IT , Mitsuya H
Ref : Journal of Medicinal Chemistry , 61 :4561 , 2018
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.

PubMedSearch : Ghosh_2018_J.Med.Chem_61_4561
PubMedID: 29763303

Related information

Citations formats

Ghosh AK, P RN, Kovela S, Rao KV, Brindisi M, Osswald HL, Amano M, Aoki M, Agniswamy J, Wang YF, Weber IT, Mitsuya H (2018)
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 61 :4561

Ghosh AK, P RN, Kovela S, Rao KV, Brindisi M, Osswald HL, Amano M, Aoki M, Agniswamy J, Wang YF, Weber IT, Mitsuya H (2018)
Journal of Medicinal Chemistry 61 :4561