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Synthesis of Novel Fluoro Analogues of MKC442 as Microbicides

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journal contribution
posted on 26.06.2014 by Yasser M. Loksha, Erik B. Pedersen, Roberta Loddo, Giuseppina Sanna, Gabriella Collu, Gabriele Giliberti, Paolo La Colla
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.