Design, Synthesis and Evaluation of Novel (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as Antitumor Agents

Abstract

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.