Design and Synthesis of a Diarylpyrimidine Bearing Bicyclic Left Wing as HIV-1 Inhibitor

Abstract

鉴于3,4-亚甲二氧苯基片段在许多药物中均为重要的药效团，本研究以经典的二芳基嘧啶类HIV-1抑制剂代表性化合物TMC125为先导化合物，将其左翼苯基替换为3,4-亚甲二氧苯基设计得到具有双环左翼的目标分子，以期得到活性更佳的新化合物。分子对接验证了设计的合理性。目标化合物的合成方法如下：以2-硫脲嘧啶为起始原料，通过三步反应得到关键中间体2-(对氰基苯胺基)-4-氯嘧啶；该中间体与芝麻酚发生亲核取代反应得到目标化合物，收率为89%。采用核磁共振氢谱(1H NMR)、核磁共振碳谱(13C NMR)和质谱(MS)表征了其结构。 Considering that 3,4-methylenedioxyphenyl fragment was an important pharmacophore in many drugs, in this work, the left wing phenyl of TMC125 as lead compound, a representative compound of classical diarylpyrimidine HIV-1 inhibitors, was replaced by 3,4-methylenedioxyphenyl to design a new target molecule bearing a bicyclic left wing, which is aimed to obtain a new compound with better biological activities. Molecular docking verified the rationality of this design. The synthetic method of the target compound was as follows: firstly, the key intermediate 2-(4-cyanoani-lino)-4-chloropyrimidine was prepared via three-step reactions from 2-thiouracil as the starting material. Next, the nucleophilic substitution of sesamol with the intermediate afforded the target compound in a yield of 89%, which was characterized by 1H NMR, 13C NMR and MS.