Department of Chemistry, University of Patras, Patras 26500, Greece.
Molecules. 2013 Jun 27;18(7):7510-32. doi: 10.3390/molecules18077510.
In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity.
在本工作中，描述了一种简便有效的合成一系列 N-取代咪唑衍生物的方法。对接研究表明，基于(E)-尿刊酸的 N-取代咪唑衍生物可能是潜在的抗高血压先导化合物。因此，合成了一系列在 N-1 或 N-3 位带有苄基或联苯甲基部分、在 C-4 位带有 (E)-丙烯酸盐或丙酸盐片段及其相关酸以及咪唑环的 C-5 位带有卤素原子的新型 AT1 受体阻滞剂。新合成的类似物被评估对人 AT1 受体的结合活性。生物实验结果表明，该类分子具有中等或无活性，因此并不总是与高对接评分一致。尽管如此，仍可以从其作用模式的分子基础中得出重要结论，并帮助药物化学家设计和合成更有效的化合物。类似洛沙坦中的脂肪族基团对于增强结合亲和力和活性似乎很重要。
