Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, PR China.
ChemMedChem. 2011 May 2;6(5):826-33. doi: 10.1002/cmdc.201000555. Epub 2011 Feb 14.
A series of new 5-alkyl-2-phenylaminocarbonylmethylthiopyrimidin-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)carbonylmethylthio]-6-(2-chloro-6-fluorobenzyl)-5-ethylpyrimidin-4(3H)-one 4 b6 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 μM (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.
一系列新型 5-烷基-2-苯氨基羰基甲基硫代嘧啶-4(3H)-酮被合成，并在 MT-4 细胞中评估其抗 HIV 活性。这些新的同系物大多数对野生型病毒表现出中等至良好的活性，EC(50)值在 1.40-0.19 μM 范围内。其中，2-[(4-氰基苯氨基)羰基甲基硫代]-6-(2-氯-6-氟苄基)-5-乙基嘧啶-4(3H)-酮 4b6 是具有最高广谱 HIV-1 抑制活性的化合物之一，对野生型病毒的 EC(50)值为 0.19±0.005 μM，对 E138K 株的抗性为 1.05±0.24 μM（两倍抗性），对 Y181C 株的抗性为 2.38±0.13 μM（4.5 倍抗性）。此外，用选定的衍生物进行了针对野生型 HIV-1 RT 的逆转录酶（RT）抑制测定，证实这些化合物的主要靶标是 HIV-1 RT，这些新的 S-DABO 类似物是作为非核苷 RT 抑制剂（NNRTIs）。还讨论了这些新同系物的构效关系和分子建模分析。
