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.
| Original language | English |
|---|---|
| Pages (from-to) | 7697-7710 |
| Number of pages | 14 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 49 |
| Issue number | 26 |
| DOIs | |
| Publication status | Published - 28 Dec 2006 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
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. / Whiting, Matthew; Tripp, Jonathan C.; Lin, Ying Chuan; Lindstrom, William; Olson, Arthur J.; Elder, John H.; Sharpless, K. Barry; Fokin, Valery V.
In: Journal of Medicinal Chemistry, Vol. 49, No. 26, 28.12.2006, p. 7697-7710.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Whiting, Matthew
AU - Tripp, Jonathan C.
AU - Lin, Ying Chuan
AU - Lindstrom, William
AU - Olson, Arthur J.
AU - Elder, John H.
AU - Sharpless, K. Barry
AU - Fokin, Valery V.
PY - 2006/12/28
Y1 - 2006/12/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33845939348&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845939348&partnerID=8YFLogxK
U2 - 10.1021/jm060754+
DO - 10.1021/jm060754+
M3 - Article
C2 - 17181152
AN - SCOPUS:33845939348
VL - 49
SP - 7697
EP - 7710
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 26
ER -