Structure-based design: synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors.
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.
Ghosh
Arun K
AK
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA. arunghos@uic.edu
Swanson
Lisa M
LM
Cho
Hanna
H
Leshchenko
Sofiya
S
Hussain
Khaja Azhar
KA
Kay
Stephanie
S
Walters
D Eric
DE
Koh
Yasuhiro
Y
Mitsuya
Hiroaki
H
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
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