Abstract

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4–24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59–14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI₅₀) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC₅₀) of 2.97 and 6.94 μM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC₅₀ = 0.2 and 0.19 μM, respectively) and HER2 (IC₅₀ = 0.13 and 0.07 μM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.

摘要

腙是一种生物活性药效团，可用于设计抗肿瘤剂。我们合成了一系列包含 4-甲基磺酰苯支架的腙（化合物4-24），并分析了它们的潜在抗肿瘤活性。化合物6，9，16，和20有最抗肿瘤活性的52/59，27/59，59/59的正的细胞毒性作用（PCE），和59/59，分别，而化合物5，10，14，15，18，和19具有适中的抗肿瘤活性为11 / 59-14 / 59的PCE。化合物20是最活跃的，平均 50% 的细胞生长抑制 (GI ₅₀ ) 为 0.26 µM。化合物9和20对COX-2的抑制活性最高，半数抑制浓度(IC ₅₀ )分别为2.97和6.94 μM。化合物16和20显着抑制EGFR（分别为IC ₅₀ = 0.2和0.19 μM）和HER2（分别为IC ₅₀ = 0.13和0.07 μM）。衍生物的分子对接研究9，16，和20 进入COX-2，EGFR和HER2的结合位点，以探索相互作用模式和抗肿瘤活性的结构要求。