A New Structural Theme in C2-Symmetric HIV-1 Protease Inhibitors: ortho-Substituted P1/P1’ Side Chains
2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, 5303-5315 p.Article in journal (Refereed) Published
In this report, the rapid syntheses of 24 novel C2-symmetric HIV-1 protease inhibitors are described. Two ortho-iodobenzyloxy containing C-terminal duplicated inhibitors served as starting materials for microwave-enhanced palladium(0)-catalyzed carbon-carbon bond forming reactions (Suzuki, Sonogashira, Heck, and Negishi). Highly potent inhibitors equipped with ortho-functionalized P1/P1' side chains as the structural theme were identified. Computational efforts were applied to study the binding mode of this class of inhibitors and to establish structure-activity relationships. The overall orientation of the inhibitors in the active site was reproduced by docking which suggested three possible conformations of the P1/P1' groups of which two seem more plausible.
Place, publisher, year, edition, pages
2006. Vol. 14, no 15, 5303-5315 p.
Amides/chemical synthesis/*chemistry/pharmacology, Catalysis, Computer Simulation, Crystallography; X-Ray, Drug Design, HIV Protease/*chemistry/drug effects, HIV Protease Inhibitors/*chemical synthesis/*chemistry/pharmacology, Microwaves, Models; Molecular, Molecular Structure, Palladium/chemistry, Quantitative Structure-Activity Relationship, Stereoisomerism
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-93076PubMedID: 16621572OAI: oai:DiVA.org:uu-93076DiVA: diva2:166443