title: Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1-P2 ligands.
abstract: A series of potent macrocyclic HIV-1 protease inhibitors have been designed and synthesized. The compounds incorporated 16- to 19-membered macrocyclic rings between a nelfinavir-like P2 ligand and a tyrosine side chain containing a hydroxyethylamine sulfonamide isostere. All cyclic inhibitors are more potent than their corresponding acyclic counterparts. Saturated derivatives showed slight reduction of potency compared to the respective unsaturated derivatives. Compound containing a 16-membered ring as the P1-P2 ligand showed the most potent enzyme inhibitory and antiviral activity.
authors: Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. akghosh@purdue.edu.
authors: Arun K
authors: AK
authors: Ghosh
authors: Gary E
authors: GE
authors: Schiltz
authors: Linah N
authors: LN
authors: Rusere
authors: Heather L
authors: HL
authors: Osswald
authors: D Eric
authors: DE
authors: Walters
authors: Masayuki
authors: M
authors: Amano
authors: Hiroaki
authors: H
authors: Mitsuya
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis; D020134:Catalytic Domain; D002460:Cell Line; D000069454:Darunavir; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D019888:Nelfinavir / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D014443:Tyrosine / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D008024:Ligands; D013449:Sulfonamides; D014443:Tyrosine; D019888:Nelfinavir; D000069454:Darunavir