Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, PR China.
ChemMedChem. 2011 Dec 9;6(12):2225-32. doi: 10.1002/cmdc.201100334. Epub 2011 Sep 8.
A series of novel diarylpyrimidines (DAPYs) with a ketone hydrazone substituent on the methylene linker between the pyrimidine nucleus and the aryl moiety at the C-4 position were synthesized, and their antiviral activity against human immunodeficiency virus (HIV)-1 in MT-4 cells was evaluated. Most compounds of this class exhibited excellent activity against wild-type HIV-1, with EC(50) values in the range of 1.7-13.2 nM. Of these compounds, 2-bromophenyl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazone (9k) displayed the most potent anti-HIV-1 activity (EC(50) =1.7±0.6 nM), with excellent selectivity for infected over uninfected cells (SI=5762). In addition, the 4-methyl phenyl analogue 9d (EC(50) =2.4±0.2 nM, SI=18461) showed broad spectrum HIV inhibitory activity, with EC(50) values of 2.4±0.2 nM against wild-type HIV-1, 5.3±0.4 μM against HIV-1 double-mutated strain RES056 (K103N+Y181C), and 5.5 μM against HIV-2 ROD strain. Furthermore, structure-activity relationship (SAR) data and molecular modeling results for these compounds are also discussed.
我们合成了一系列新型的嘧啶并[4,5-d]嘧啶酮（DAPYs），其嘧啶核和 C-4 位芳基部分之间的亚甲基连接链上带有酮腙取代基，并评估了它们对人免疫缺陷病毒（HIV-1）在 MT-4 细胞中的抗病毒活性。该类化合物大多数对野生型 HIV-1 具有优异的活性，EC50 值在 1.7-13.2 nM 范围内。在这些化合物中，2-溴苯基-2-[(4-氰基苯基)氨基]-4-嘧啶酮腙（9k）表现出最强的抗 HIV-1 活性（EC50=1.7±0.6 nM），对感染细胞与未感染细胞具有极好的选择性（SI=5762）。此外，4-甲基苯基类似物 9d（EC50=2.4±0.2 nM，SI=18461）显示出广谱的 HIV 抑制活性，对野生型 HIV-1 的 EC50 值为 2.4±0.2 nM，对 HIV-1 双突变株 RES056（K103N+Y181C）的 EC50 值为 5.3±0.4 μM，对 HIV-2 ROD 株的 EC50 值为 5.5 μM。此外，还讨论了这些化合物的构效关系（SAR）数据和分子建模结果。
