合成新型氟代 MKC442 类似物作为杀微生物剂。

Synthesis of novel fluoro analogues of MKC442 as microbicides.

机构信息

Nucleic Acid Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.

出版信息

J Med Chem. 2014 Jun 26;57(12):5169-78. doi: 10.1021/jm500139a. Epub 2014 Jun 3.

DOI:10.1021/jm500139a

PMID:24805780

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.

摘要

通过 6-[(3,5-二甲基苯基)氟甲基]-5-乙基尿嘧啶（5）与氯乙氧基甲和甲醛缩醛的反应，合成了 MKC442（6-苄基-1-（乙氧甲基）-5-异丙基嘧啶-2,4(1H,3H)-二酮）的新型类似物。对化合物 5 的 N1-[(对碘苄基)氧基]甲基衍生物进行了 Sonogashira 反应，使用丙醇得到化合物 12（YML220）。选择后者进行进一步研究，因为它在体外对野生型 HIV-1 以及非核苷逆转录酶抑制剂、核苷逆转录酶抑制剂和蛋白酶抑制剂耐药突变体和广泛的 HIV-1 临床分离株显示出最有效和选择性的活性。12 在感染严重的 MT-4 细胞的长期试验中也表现出杀菌活性。