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

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

Bioorganic & medicinal chemistry 2008 Apr 1

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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.

Citation

Zhengqiang Wang, Robert Vince. Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: introducing a diketoacid functionality into delavirdine. Bioorganic & medicinal chemistry. 2008 Apr 1;16(7):3587-95