910909-96-5Relevant academic research and scientific papers
Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2?ligand: Structure?activity studies and biological evaluation
Bai, Xiaoguang,Yang, Zhiheng,Zhu, Mei,Dong, Biao,Zhou, Lei,Zhang, Guoning,Wang, Juxian,Wang, Yucheng
, p. 30 - 44 (2017/05/31)
The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary amine P2-ligand and phenylsulfonamide P2′-ligand were investigated to maximize the ligand-binding site interactions in the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide as P2′-ligand displayed the most potent enzyme inhibitory activity (IC50 = 0.35 nM) and remarkably low cytotoxicity (CC50 = 305 μM).
Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones
Ali, Akbar,Reddy, G. S. Kiran Kumar,Nalam, Madhavi N. L.,Anjum, Saima Ghafoor,Cao, Hong,Schiffer, Celia A.,Rana, Tariq M.
scheme or table, p. 7699 - 7708 (2010/12/30)
A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different phenyloxazolidinone P2 ligands were designed and synthesized. Variation of phenyl substitutions at the P2 and P2' moieties significantly affected the binding affinity and antiviral potency of the inhibitors. In general, compounds with 2- and 4-substituted phenyloxazolidinones at P2 exhibited lower binding affinities than 3-substituted analogues. Crystal structure analyses of ligand-enzyme complexes revealed different binding modes for 2- and 3-substituted P2 moieties in the protease S2 binding pocket, which may explain their different binding affinities. Several compounds with 3-substituted P2 moieties demonstrated picomolar binding affinity and low nanomolar antiviral potency against patient-derived viruses from HIV-1 clades A, B, and C, and most retained potency against drug-resistant viruses. Further optimization of these compounds using structure-based design may lead to the development of novel protease inhibitors with improved activity against drug-resistant strains of HIV-1.
Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance
Ghosh, Arun K.,Sridhar, Perali Ramu,Leshchenko, Sofiya,Hussain, Azhar K.,Li, Jianfeng,Kovalevsky, Andrey Yu.,Walters, D. Eric,Wedekind, Joseph E.,Grum-Tokars, Valerie,Das, Debananda,Koh, Yasuhiro,Maeda, Kenji,Gatanaga, Hiroyuki,Weber, Irene T.,Mitsuya, Hiroaki
, p. 5252 - 5261 (2008/02/11)
Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b] furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[e]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 ? resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
