Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: introducing a diketoacid functionality into delavirdine

Zhengqiang Wang; Robert Vince

doi:10.1016/j.bmc.2008.02.007

Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: introducing a diketoacid functionality into delavirdine

Bioorg Med Chem. 2008 Apr 1;16(7):3587-95. doi: 10.1016/j.bmc.2008.02.007. Epub 2008 Feb 8.

Authors

Zhengqiang Wang¹, Robert Vince

Affiliation

¹ Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, MN 55455, USA. wangx472@umn.edu

PMID: 18314335
DOI: 10.1016/j.bmc.2008.02.007

Abstract

Cost and toxicity problems associated with highly active antiretroviral therapy (HAART) in HIV/AIDS treatment could be alleviated by using designed multiple ligands (DMLs). Dual inhibitors of HIV reverse transcriptase (RT) and integrase (IN) were rationally designed by introducing a diketoacid (DKA) functionality into the tolerant C-5 site of RT inhibitor delavirdine. The resulting compounds all demonstrate good activity against both RT and IN in enzymatic assays and HIV in cell-based assay, whereas their C-7 regioisomers are all inactive in these assays. Balanced activities were observed with C-3 halogenated inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Delavirdine / chemistry*
Drug Design*
HIV / drug effects
HIV / enzymology
HIV Integrase / metabolism
HIV Integrase Inhibitors / chemical synthesis*
HIV Integrase Inhibitors / chemistry
HIV Integrase Inhibitors / pharmacology*
HIV Reverse Transcriptase / antagonists & inhibitors
HIV Reverse Transcriptase / metabolism
Keto Acids / chemistry*
Molecular Structure
Reverse Transcriptase Inhibitors / chemical synthesis*
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*

Substances

HIV Integrase Inhibitors
Keto Acids
Reverse Transcriptase Inhibitors
Delavirdine
HIV Integrase
HIV Reverse Transcriptase