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JAC Advance Access published online on November 22, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl454
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received June 29, 2006
Revised September 14, 2006
Accepted October 10, 2006

Original article

Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy] pyrimidines

Jan Balzarini 1 *, Dominique Schols 1, Kristel Van Laethem 1, Erik De Clercq 1, Dana Hocková 2, Milina Masojidkova 2, and Antonin Holy 2

1 Rega Institute for Medical Research, K.U.Leuven, B-3000 Leuven, Belgium
2 Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Praha, Czech Republic

* To whom correspondence should be addressed.
Jan Balzarini, E-mail: jan.balzarini{at}rega.kuleuven.be


  Abstract

Objectives: To discover new potent and selective anti-human immunodeficiency virus (HIV) acyclic nucleoside phosphonate (ANP) drugs with in vivo antiretroviral activity.

Methods: New acyclic pyrimidine nucleoside phosphonate derivatives that mimic the structure of the anti-HIV purine nucleoside phosphonates 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir) and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA, tenofovir) were designed by linking the acyclic side chain of the ANPs through an ether bond to the C-6 position instead of the N-1 position of the pyrimidine ring. The compounds were evaluated against HIV and Moloney murine sarcoma virus (MSV) in cell culture, including a broad variety of HIV-1 clade clinical isolates and relevant mutant (drug-resistant) HIV-1 isolates. Their antiviral activities were correlated and investigated in an in vivo model consisting of MSV-infected newborn mice. MSV-induced tumour formation and associated death were recorded in drug-treated animals.

Results: Several 5-substituted 6-[2-(phosphonomethoxy)ethoxy]-2,4-diaminopyrimidine (PMEO-DAPy) analogues were found to inhibit a broad variety of HIV-1 clinical isolates. They showed a more favourable cross-resistance profile to mutant virus isolates than adefovir and tenofovir. There was a close correlation between inhibition of MSV in C3H/3T3 cells and inhibition of HIV-1 in CEM cells. The PMEO-DAPy derivatives potently inhibited MSV-induced tumour cell formation in newborn mice. The 5-methyl analogue PMEO-5-Me-DAPy proved markedly more inhibitory to MSV-induced tumour cell formation and associated animal death than its unsubstituted parent PMEO-DAPy derivative. When compared with adefovir, PMEO-5-Me-DAPy was less toxic and more antivirally active in MSV-infected mice.

Conclusions: PMEO-5-Me-DAPy deserves further (pre)clinical investigations as a candidate anti-HIV drug.

Keywords: HIV; MSV; acyclic nucleoside phosphonates; ANP; antiretroviral drugs; PMEO-DAPy.
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