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Antimicrobial Agents and Chemotherapy, January 2008, p. 225-236, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00972-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Comparative Evaluation of the Inhibitory Activities of a Series of Pyrimidinedione Congeners That Inhibit Human Immunodeficiency Virus Types 1 and 2{triangledown}

Robert W. Buckheit Jr.,1* Tracy L. Hartman,1 Karen M. Watson,1 Sun-Gan Chung,2 and Eui-Hwan Cho2

ImQuest BioSciences, Inc., 7340 Executive Way, Suite R, Frederick, Maryland 21704,1 Samjin Pharmaceutical Company, Ltd., Seoul, South Korea2

Received 26 July 2007/ Returned for modification 14 September 2007/ Accepted 22 October 2007

Seventy-three analogs of SJ-3366 (1-(3-cyclopenten-1-ylmethyl)-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4(1H,3H)-pyrimidinedione) were synthesized and comparatively evaluated for their ability to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 and for their ability to suppress virus entry and reverse transcription. These studies were performed to identify inhibitors with activity greater than that of the current lead molecule (SJ-3366) and to utilize structure-activity relationships (SAR) to define the chemical features of the pyrimidinedione congeners responsible for their efficacy, toxicity, and dual mechanism of action against HIV. The results of our SAR evaluations have demonstrated that the addition of the homocyclic moiety at the N-1 of the pyrimidinedione results in acquisition of the ability to inhibit virus entry and extends the range of action of the compounds to include HIV-2. In addition, the results demonstrate that analogs with a methyl linker between the homocyclic substitution and the N-1 of the pyrimidinedione had a greater number of highly active molecules than those analogs possessing ethyl linkers. Six molecules were identified with activity equivalent to or greater than that of SJ-3366, and five additional molecules with highly potent inhibition of reverse transcriptase and virus entry and possessing high efficacy against both HIV-1 and HIV-2 were identified. Six molecules exhibited significant inhibition of viruses with the highly problematic nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance engendering amino acid change K103N in the reverse transcriptase. These evaluations indicate that a new class of NNRTIs has been identified and that these NNRTIs possess highly potent inhibition of HIV-1 with an extended range of action, which now includes HIV-2.

* Corresponding author. Mailing address: ImQuest BioSciences, Inc., 7340 Executive Way, Suite R, Frederick, MD 21704. Phone: (301) 696-0274. Fax: (301) 696-0381. E-mail: rbuckheit{at}imquest.com

{triangledown} Published ahead of print on 29 October 2007.

Antimicrobial Agents and Chemotherapy, January 2008, p. 225-236, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00972-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Watson, K. M., Buckheit, C. E., Buckheit, R. W. Jr. (2008). Comparative Evaluation of Virus Transmission Inhibition by Dual-Acting Pyrimidinedione Microbicides Using the Microbicide Transmission and Sterilization Assay. Antimicrob. Agents Chemother. 52: 2787-2796 [Abstract] [Full Text]  


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