Synthesis of Novel Fluoro Analogues of MKC442 as Microbicides

Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4­(1<i>H</i>,3<i>H</i>)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)­fluoromethyl]-5-ethyluracil (<b>5</b>) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the <i>N</i>1-(<i>p</i>-iodobenzyl)­oxy]­methyl derivative of compound <b>5</b> using propagyl alcohol to afford compound <b>12</b> (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. <b>12</b> also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.