title: Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization.
abstract: Building from the results of a computational screen of a range of triazole-containing compounds for binding efficiency to human immunodeficiency virus type 1 protease (HIV-1-Pr), a novel series of potent inhibitors has been developed. The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), which provides ready access to 1,4-disubstituted-1,2,3-triazoles, was used to unite a focused library of azide-containing fragments with a diverse array of functionalized alkyne-containing building blocks. In combination with direct screening of the crude reaction products, this method led to the rapid identification of a lead structure and readily enabled optimization of both azide and alkyne fragments. Replacement of the triazole with a range of alternative linkers led to greatly reduced protease inhibition; however, further functionalization of the triazoles at the 5-position gave a series of compounds with increased activity, exhibiting Ki values as low as 8 nM.
authors.affiliation: Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiting
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Tripp
authors.forename: Ying-Chuan
authors.initials: YC
authors.lastname: Lin
authors.forename: William
authors.initials: W
authors.lastname: Lindstrom
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Olson
authors.forename: John H
authors.initials: JH
authors.lastname: Elder
authors.forename: K Barry
authors.initials: KB
authors.lastname: Sharpless
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
mesh_terms: D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D003300:Copper / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015658:HIV Infections / Q000188:drug therapy; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication
chemical_list: D017320:HIV Protease Inhibitors; D014230:Triazoles; D003300:Copper; D016333:HIV Protease