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

Matthew Whiting, Jonathan C. Tripp, Ying Chuan Lin, William Lindstrom, Arthur J. Olson, John H. Elder, K. Barry Sharpless, Valery V. Fokin

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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.

Original languageEnglish
Pages (from-to)7697-7710
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number26
Publication statusPublished - 28 Dec 2006
Externally publishedYes


ASJC Scopus subject areas

  • Organic Chemistry

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