Synthesis of novel fluoro analogues of MKC442 as microbicides

  • J Med Chem. 2014 Jun 26;57(12):5169-78. doi: 10.1021/jm500139a.
Yasser M Loksha  1 ,  Erik B Pedersen ,  Roberta Loddo ,  Giuseppina Sanna ,  Gabriella Collu ,  Gabriele Giliberti ,  Paolo La Colla
Affiliations
  • 1. Nucleic Acid Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
PMID: 24805780 DOI: 10.1021/jm500139a
Abstract

Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside Reverse Transcriptase inhibitor-, nucleoside Reverse Transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.