title: Synthesis of novel fluoro analogues of MKC442 as microbicides.
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.
authors.affiliation: Nucleic Acid Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Yasser M
authors.initials: YM
authors.lastname: Loksha
authors.forename: Erik B
authors.initials: EB
authors.lastname: Pedersen
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sanna
authors.forename: Gabriella
authors.initials: G
authors.lastname: Collu
authors.forename: Gabriele
authors.initials: G
authors.lastname: Giliberti
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D024882:Drug Resistance, Viral; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D009154:Mutation; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000591341:6-((3,5-dimethylphenyl)fluoromethyl)-5-ethyl-1-(((4-(3-hydroxyprop-1-ynyl)benzyl)oxy)methyl)pyrimidine-2,4(1H,3H)-dione; D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; D054303:HIV Reverse Transcriptase; C083858:emivirine