BACKGROUND Herein, we have designed and synthesized a series of the novel (E)-N'-((1-(4-chlorobenzyl)- 1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5) as potent small molecules activating procaspase- 3. The compounds were designed by the amalgamation of structural features of PAC-1 (the first procaspase-3 activator) and oncrasin-1, one potential anticancer agent. METHODS The target acetohydrazides (5a-m) were prepared via the Niementowski condensation of anthranilic acid (1a) or 5-substituted-2-aminobenzoic acid (1b-m) and formamide. The compound libraries were evaluated for their cytotoxicity, caspase-3 activation, cell cycle analysis, and apoptosis. In addition, computational chemistry is also performed. RESULTS A biological evaluation revealed that all thirteen compounds designed and synthesized showed strong cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer) with eight compounds (5a, 5c-i, 5k), which were clearly more potent than both PAC-1 and oncrasin-1. In this series, four compounds, including 5c, 5e, 5f, and 5h, were the most potent members with approximately 4- to 5-fold stronger than the reference compounds PAC-1 and oncrasin-1 in terms of IC50. In comparison to 5-FU, these compounds were even 18- to 29-fold more potent in terms of cytotoxicity in three human cell lines tested. In the caspase activation assay, the caspase activity was activated to 285% by compound 5e compared to PAC-1, the first procaspase activating compound, which was used as a control. Our docking simulation revealed that compound 5e was a potent allosteric inhibitor of procaspase-3 through chelation of inhibitory zinc ion. Physicochemical and ADMET calculations for 5e provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent. CONCLUSION Compound 5e has emerged as a potential hit for further design and development of caspases activators and anticancer agents.

中文翻译：

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新型 (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides 的设计、合成和评价作为抗肿瘤剂。

背景在此，我们设计合成了一系列新型的(E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3( 4H)-yl)acetohydrazides (5) 作为有效的小分子激活 procaspase-3。这些化合物是通过融合 PAC-1（第一个 procaspase-3 激活剂）和 oncrasin-1（一种潜在的抗癌剂）的结构特征而设计的。方法通过邻氨基苯甲酸(1a)或5-取代-2-氨基苯甲酸(1b-m)与甲酰胺的Niementowski缩合制备目标乙酰肼(5a-m)。评估了化合物库的细胞毒性、caspase-3 活化、细胞周期分析和细胞凋亡。此外，还进行了计算化学。结果 生物学评估表明，所有设计和合成的 13 种化合物对 3 种人类癌细胞系（SW620，结肠癌；PC-3，前列腺癌；NCI-H23，肺癌）与 8 种化合物（5a、5c-i）均显示出强烈的细胞毒性。 , 5k), 这显然比 PAC-1 和 oncrasin-1 更有效。在该系列中，包括 5c、5e、5f 和 5h 在内的四种化合物是最有效的成员，其 IC50 比参考化合物 PAC-1 和 oncrasin-1 强约 4 至 5 倍。与 5-FU 相比，这些化合物在测试的三种人类细胞系中的细胞毒性甚至高出 18 到 29 倍。在半胱天冬酶活化测定中，半胱天冬酶活性被化合物 5e 激活至 285%，而 PAC-1 是用作对照的第一个 procaspase 活化化合物。我们的对接模拟表明，化合物 5e 通过螯合抑制性锌离子是 procaspase-3 的有效变构抑制剂。5e 的物理化学和 ADMET 计算提供了有关其合适的吸收曲线和一些毒理学效应的有用信息，这些信息需要进一步优化才能开发为有前途的抗癌剂。结论 化合物 5e 已成为进一步设计和开发半胱天冬酶激活剂和抗癌剂的潜在目标。