标题：Synthesis and Biological Evaluation of 6-Substituted 5-Alkyl-2-(phenylaminocarbonylmethylthio)pyrimidin-4(3H)- ones as Potent HIV-1 NNRTIs
作者：Mingyan Yu;Zhenyu Li;Shuai Liu
作者机构：[Yu, M] Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, No.44 Wenhuaxi Road, Jinan 250012, China;[ Li, Z] In 更多
通讯作者地址：[Yu, MY]Shandong Univ, Sch Pharmaceut Sci, Inst Med Chem, 44 Wenhuaxi Rd, Jinan 250012, Peoples R China.
关键词：antiviral agents;DABOs;HIV-1;medicinal chemistry;NNRTIs
摘要：A series of new 5-alkyl-2-phenylaminocarbonylmethylthiopyri-midin-4(3H)-ones bearing variously substituted arylmethyl moieties at the C6 position of the pyrimidine ring were synthesized and evaluated for anti-HIV activity in MT-4 cells. Most of these new congeners exhibited moderate to good activities against the wild-type virus, with EC_(50) values in the range of 1.40-0.19 μm. Among them, 2-[(4-cyanophenylamino)carbonyl-methylthio]-6-(2-chloro-6-fluorobenzyl)-5-ethylpyrimidin-4(3H)-one 4b6 is one of the compounds endowed with the highest broad-spectrum HIV-1 inhibitory activity, with EC_(50) values of 0.19 ± 0.005 μM against the wild-type virus, 1.05 ±0.24 μM (twofold resistance) against the E138K strain, and 2.38 ± 0.13 um (4.5-fold resistance) against the Y181C strain. Furthermore, reverse transcriptase (RT) inhibition assays against wild-type HIV-1 RT were performed with selected derivatives, confirming that the main target of these compounds is HIV-1 RT and that these new S-DABO analogues act as non-nucleoside RT inhibitors (NNRTIs). Structure-activity relationship and molecular modeling analyses of these new congeners are also discussed.