Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: introducing a diketoacid functionality into delavirdine.
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.
Wang
Zhengqiang
Z
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, MN 55455, USA. wangx472@umn.edu
Vince
Robert
R
D020008:Delavirdine / Q000737:chemistry*; D015195:Drug Design; D006678:HIV / Q000187:drug effects / Q000201:enzymology; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007651:Keto Acids / Q000737:chemistry*; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D018894:Reverse Transcriptase Inhibitors; D020008:Delavirdine; D019427:HIV Integrase; D054303:HIV Reverse Transcriptase