%0 Generic
%A Ghosh, Arun K.
%A Nyalapatla, Prasanth R.
%A Kovela, Satish
%A Rao, Kalapala Venkateswara
%A Brindisi, Margherita
%A Osswald, Heather L.
%A Amano, Masayuki
%A Aoki, Manabu
%A Agniswamy, Johnson
%A Wang, Yuan-Fang
%A Weber, Irene T.
%A Mitsuya, Hiroaki
%D 2018
%T 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
%U https://acs.figshare.com/articles/dataset/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/6270338
%R 10.1021/acs.jmedchem.8b00298.s002
%2 https://acs.figshare.com/ndownloader/files/11458070
%K protease inhibitors
%K ring sizes
%K substituent effects
%K Novel P 2 Ligands
%K umbrella-like P 2 ligand
%K resolution X-ray structures
%K multidrug-resistant HIV
%K racemic alcohols
%K backbone atoms
%K binding properties
%K P 1 ligand
%K sulfonamide derivatives
%K P 2 ligands
%K tricyclic polyethers
%K P 2 ligand
%K inhibitor-bound HIV
%K Inhibitors 5 c
%X 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.
%I ACS Publications