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Antimicrobial Agents and Chemotherapy, December 1998, p. 3225-3233, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Structure-Based Design of Novel Dihydroalkoxybenzyloxopyrimidine Derivatives as Potent Nonnucleoside Inhibitors of the Human Immunodeficiency Virus Reverse Transcriptase

Elise A. Sudbeck,1,2,3 Chen Mao,1,3 Rakesh Vig,1,2 T. K. Venkatachalam,1,2 Lisa Tuel-Ahlgren,4 and Fatih M. Uckun1,4,*

Drug Discovery Program,1 Departments of Chemistry,2 Structural Biology,3 and Virology,4 Hughes Institute, St. Paul, Minnesota 55113

Received 7 April 1998/Returned for modification 5 June 1998/Accepted 5 October 1998

Two highly potent dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket and tested for anti-HIV activity. Our lead DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-one, elicited potent inhibitory activity against purified recombinant HIV RT and abrogated HIV replication in peripheral blood mononuclear cells at nanomolar concentrations (50% inhibitory concentration, <1 nM) but showed no detectable cytotoxicity at concentrations as high as 100 µM.

* Corresponding author. Mailing address: Hughes Institute, 2665 Long Lake Road, Suite 330, St. Paul, MN 55113. Phone: (651) 697-9228. Fax: (651) 697-1042. E-mail: fatih_uckun{at}mercury.ih.org.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3225-3233, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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