title: Structure-based design: synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors.
abstract: The structure-based design and synthesis of a series of novel nonpeptide HIV protease inhibitors are described. The inhibitors were designed based upon the X-ray crystal structure of inhibitor 1 (UIC-94017)-bound HIV-1 protease. The inhibitors incorporated 3-hydroxysalicyclic acid-derived acyclic and cyclic P2 ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. The inhibitors contain only two chiral centers and are readily synthesized in optically active form utilizing Sharpless asymmetric epoxidation, regioselective epoxide opening, and ring-closing olefin metathesis using Grubbs' catalyst as the key steps. We have synthesized 13-15-membered cycloamides and evaluated their HIV-1 protease enzyme inhibitory and antiviral activities in MT-2 cells. Interestingly, all cycloamide-derived inhibitors are noticeably more potent than the corresponding acyclic compounds. The ring size and substituent effects were investigated. It turned out that the 14-membered saturated ring is preferred by the S(1)-S(2) active sites of HIV-1 protease. Macrocycle 26 showed excellent enzyme inhibitory potency with a K(i) value of 0.7 nM and an antiviral IC(50) value of 0.3 microM. In view of their structural simplicity and preliminary interesting results, further optimization of these inhibitors is underway.
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA. arunghos@uic.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Swanson
authors.forename: Hanna
authors.initials: H
authors.lastname: Cho
authors.forename: Sofiya
authors.initials: S
authors.lastname: Leshchenko
authors.forename: Khaja Azhar
authors.initials: KA
authors.lastname: Hussain
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kay
authors.forename: D Eric
authors.initials: DE
authors.lastname: Walters
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D016333:HIV Protease; D017320:HIV Protease Inhibitors; D007769:Lactams; D047029:Lactams, Macrocyclic; D013449:Sulfonamides; C500840:N-(2''-hydroxy-2''-(4-hydroxy-16-oxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-15-azabenzocyclotetradecen-14-yl)ethyl)-N-isobutyl-4-methoxybenzenesulfonamide; D000096926:Benzenesulfonamides