Mao Tian-Qi, He Qiu-Qin, Wan Zheng-Yong, Chen Wen-Xue, Chen Fen-Er, Tang Gang-Feng, De Clercq Erik, Daelemans Dirk, Pannecouque Christophe
Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Institute of Biomedical Science, Fudan University, Shanghai 200433, People's Republic of China.
Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
Bioorg Med Chem. 2015 Jul 1;23(13):3860-8. doi: 10.1016/j.bmc.2015.03.037. Epub 2015 Apr 6.
A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07μM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules.
分子杂交方法是设计具有更高亲和力和效力的新分子的有力工具。在此背景下，合成了一系列二芳基嘧啶 - 喹诺酮杂合物，并针对野生型HIV-1和突变病毒株进行了评估。活性最高的杂合物5a对HIV-1 IIIB的EC50值为0.28±0.07μM。几项基于酶的测定清楚地确定了一种靶向逆转录酶的作用机制。对接研究表明，尽管分子中的喹诺酮3-羧酸部分具有庞大且极性的性质，但这些杂合物仍可很好地定位在HIV-1逆转录酶的非核苷类抑制剂结合口袋中。
