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Antimicrobial Agents and Chemotherapy, July 2002, p. 2185-2193, Vol. 46, No. 7
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.7.2185-2193.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antiretrovirus Activity of a Novel Class of Acyclic Pyrimidine Nucleoside Phosphonates{dagger}

J. Balzarini,1* C. Pannecouque,1 E. De Clercq,1 S. Aquaro,2 C.-F. Perno,2 H. Egberink,3 and A. Holy4

Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium,1 Department of Experimental Medicine, University of Rome Tor Vergata, 00135 Rome, Italy,2 Department of Infectious Diseases and Immunology, Veterinary Faculty, 3584 CL Utrecht, The Netherlands,3 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic4

Received 26 November 2001/ Returned for modification 11 February 2002/ Accepted 8 April 2002

A novel class of acyclic nucleoside phosphonates has been discovered in which the base consists of a pyrimidine preferably containing an amino group at C-2 and C-4 and a 2-(phosphonomethoxy)ethoxy (PMEO) or a 2-(phosphonomethoxy)propoxy (PMPO) group at C-6. The 6-PMEO 2,4-diaminopyrimidine (compound 1) and 6-PMPO 2,4-diaminopyrimidine (compound 11) derivatives showed potent activity against human immunodeficiency virus (HIV) in the laboratory (i.e., CEM and MT-4 cells) and in primary (i.e., peripheral blood lymphocyte and monocyte/macrophage) cell cultures and pronounced activity against Moloney murine sarcoma virus in newborn NMRI mice. Their in vitro and in vivo antiretroviral activity was comparable to that of reference compounds 9-[(2-phosphonomethoxy)ethyl]adenine (adefovir) and (R)-9-[(2-phosphonomethoxy)-propyl]adenine (tenofovir), and the enantiospecificity of (R)- and (S)-PMPO pyrimidine derivatives as regards their antiretroviral activity was identical to that of the classical (R)- and (S)-9-(2-phosphonomethoxy)propyl purine derivatives. The prototype PMEO and PMPO pyrimidine analogues were relatively nontoxic in cell culture and did not markedly interfere with host cell macromolecular (i.e., DNA, RNA, or protein) synthesis. Compounds 1 and 11 should be considered attractive novel pyrimidine nucleotide phosphonate analogues to be further pursued for their potential as antiretroviral agents in the clinical setting.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32-16-337341. Fax: 32-16-3373340. E-mail: jan.balzarini{at}rega.kuleuven.ac.be.

{dagger} This study constitutes a part of research project 4055905 of the Institute of Organic Chemistry and Biochemistry, Prague, Czech Republic.

Antimicrobial Agents and Chemotherapy, July 2002, p. 2185-2193, Vol. 46, No. 7
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.7.2185-2193.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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