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

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.

Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease

“…DRV and analogs have been and continue to be the subject of chemical, viral, structural and dynamics studies 27 . Modifications to the bis-THF P2 moiety of DRV, including fluorine decorations, expansion to tris-THF and fusion into a tri-cyclic group 17,28,29 and additional modifications of the P1 and P2' moiety have been shown to improve potency and resistance profiles [30][31][32] . Our computational studies suggested that P1' and P2' moieties of DRV could be further optimized 33 while still staying within the substrate envelope.…”

Modern Approaches to the Synthesis and Transformations of Practically Valuable Benzothiazole Derivatives

“…2-Aminobenzothiazoles demonstrate high antiviral activity [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ], which is especially important in this period of global COVID-19 pandemic. They also possess antimicrobial [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ], antioxidant [ 20 ], anti-inflammatory [ 21 , 22 , 23 , 24 ], analgesic [ 24 ], antidepressant [ 25 , 26 ], anticonvulsant [ 27 , 28 , 29 ], anti-diabetic [ 21 , 30 ], antitumor [ 31 , 32 , 33 , 34 , 35 ], antituberculosis [ 14 , 36 ] activity.…”

Benzothiazoles as potential antiviral agents

“…The resulting analogue 32 showed excellent enzyme inhibitory potency (IC 50 27 pM) with a strong antiviral activity against a panel of highly multidrugresistant HIV 1 variants. [67] Extensive lead optimisation at the P2 0 region was aimed at improving the broad-spectrum activity as well as the overall ADME profile of these derivatives. Surleraux, et al, 2005, at Tibotec BVBA, Belgium, did parallel research exploring the P2 0 region to identify new classes of broad-spectrum PIs with improved pharmacokinetic properties.…”