Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase

J. Med. Chem., 50 (15), 3416 -3419, 2007. 10.1021/jm070512p S0022-2623(07)00512-2
Web Release Date: July 4, 2007

Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase

Zhengqiang Wang, Eric M. Bennett, Daniel J. Wilson, Christine Salomon, and Robert Vince*

Center for Drug Design, Academic Health Center, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455

Received May 2, 2007

Abstract:

Bifunctional inhibitors were designed and synthesized based on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)^a¹ non-nucleoside reverse transcriptase (RT) inhibitors and diketoacid (DKA) integrase (IN) inhibitors. Biochemical studies revealed activity against RT and IN at low nanomolar and low micromolar concentrations, respectively. Exceptionally low IC₅₀ values from a cell-based assay were achieved along with remarkably high therapeutic indices. Compound 7 was identified as the best compound of the series (IC₅₀: 24 nM against RT, 4.4 M against IN, and 10 nM against HIV-1).

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