Design, synthesis of new pyrimidine derivatives as anticancer and antimicrobial agents

A new series of 6-aryl-5-cyano thiouracil derivatives were synthesized. Cyanouracil <b>1</b> was condensed with monochloroacetic acid and different aldehydes to give thiazolopyrimidine <b>2</b>. On the other hand, treatment of cyanouracil <b>1</b> with 2-chloro-<i>N</i>-substituted-phenylac etamide afforded <b>4</b>. Hydrazinolysis of <b>6</b> afforded the hydrazino derivatives <b>7</b> which upon reaction with different electrophilic reagents such as acetic anhydride, benzoyl chloride, and carbon disulfide yielded pyrimidine derivatives <b>8</b>–<b>15</b>. Some of the new derivatives were explored for their antimicrobial activities. Compounds <b>7</b> and <b>9</b> have a promising activity, relatively equipotent to the reference drug. All of the new synthesized compounds were tested <i>in vitro</i> for their antiproliferative activities against HePG-2 and MCF-7 cell lines. Compounds <b>7</b>, <b>9</b>, and <b>2d</b> displayed potent growth inhibitory effect toward the two cell lines more than the standard drug 5-FU. Furthermore, a docking study of the most active compounds was performed with thymidylate synthase enzyme.

本研究合成了一系列全新的6-芳基-5-氰基硫尿嘧啶（6-aryl-5-cyano thiouracil）衍生物。氰基硫尿嘧啶1与一氯乙酸及不同醛类发生缩合反应，得到噻唑并嘧啶（thiazolopyrimidine）类衍生物2。另一方面，将氰基硫尿嘧啶1与2-氯-N-取代苯基乙酰胺进行反应，得到产物4。对化合物6进行肼解反应，得到肼基取代衍生物7；该衍生物与乙酸酐、苯甲酰氯、二硫化碳等亲电试剂反应后，可生成嘧啶类衍生物8~15。选取部分新型衍生物开展抗菌活性评价，结果显示化合物7与9表现出优异的抗菌活性，其效价与参比药物相当。对所有合成得到的新型化合物均开展了体外（in vitro）抗增殖活性测试，测试对象为HePG-2及MCF-7肿瘤细胞系。其中化合物7、9及2d对两种细胞系均表现出显著的生长抑制活性，其效果优于阳性对照药物5-氟尿嘧啶（5-FU）。此外，针对活性最优的化合物，本研究开展了其与胸苷酸合酶（thymidylate synthase）的分子对接研究。