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Antimicrobial Agents and Chemotherapy, October 2004, p. 3684-3689, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3684-3689.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Series of Diaryltriazines and Diarylpyrimidines Are Highly Potent Nonnucleoside Reverse Transcriptase Inhibitors with Possible Applications as Microbicides{dagger}

Yven Van Herrewege,1* Guido Vanham,1,2 Jo Michiels,1 Katrien Fransen,3 Luc Kestens,4 Koen Andries,5 Paul Janssen,6,{ddagger} and Paul Lewi6

HIV Virology Research Unit,1 AIDS Reference Laboratory,3 Laboratory of Immunology, Department of Microbiology Institute of Tropical Medicine,4 Department of Biomedical Sciences, University of Antwerp Antwerp,2 Tibotec, Mechelen,5 Center for Molecular Design, Janssen Pharmaceutica, Vosselaar Belgium6

Received 15 March 2004/ Returned for modification 27 May 2004/ Accepted 8 June 2004

An in vitro model of monocyte-derived dendritic cells (MO-DC) and CD4+ T cells, representing the primary targets of sexual human immunodeficiency virus (HIV) transmission, was used to evaluate the antiviral and immune suppressive activity of new classes of nonnucleoside reverse transcriptase inhibitors, diaryltriazines (DATAs) and diarylpyrimidines (DAPYs), compared to the reference compounds UC-781 and PMPA. Antiviral activity (as reflected by the 50% effective concentration [EC50]) was determined by treating HIV-infected MO-DC/CD4+-T-cell cocultures with a dose range of a compound during 14 days, followed by analysis of supernatants in HIV p24 antigen enzyme-linked immunosorbent assay. A limited, 24-h treatment evaluated the compounds as microbicides. Viral rescue was evaluated in a PCR by monitoring proviral DNA in secondary cultures with phytohemagglutinin-interleukin-2 blasts. We determined 50% immunosuppressive concentrations in mixed leukocyte cultures of MO-DC and allogeneic T cells, with compound either continuously present or present only during the first 24 h. The EC50 values of DATA and DAPY compounds ranged from 0.05 to 3 nM compared to 50 nM for UC-781 and 89 nM for PMPA. When evaluated in the "microbicide" setting, the most potent compounds completely blocked HIV infection at 10 to 100 nM. The immunosuppressive concentrations were well above the EC50, resulting in favorable therapeutic indices for all compounds tested. The DATA and DAPY compounds described here are more potent than earlier reverse transcriptase inhibitors and show favorable pharmacological profiles in vitro. They could strengthen the antiretroviral armamentarium and might be useful as microbicides.

* Corresponding author. Mailing address: HIV Virology Research Unit, Institute of Tropical Medicine, 155 Nationalestraat, B-2000 Antwerp, Belgium. Phone: 32-3-247-62-26. Fax: 32-3-247-62-31. E-mail: yvherrewege{at}itg.be.

{dagger} This study is dedicated to the memory of Paul A. J. Janssen, founder of Janssen Pharmaceutica and mentor of the Center for Molecular Design.

{ddagger} Deceased.

Antimicrobial Agents and Chemotherapy, October 2004, p. 3684-3689, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3684-3689.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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