Design, synthesis, and evaluation of novel (E)‐N'‐(3‐allyl‐2‐hydroxy)benzylidene‐2‐(4‐oxoquinazolin‐3(4H)‐yl)acetohydrazides as antitumor agents

Abstract

In our continuing search for novel small‐molecule anticancer agents, we designedand synthesized a series of novel (E)‐N'‐(3‐allyl‐2‐hydroxy)benzylidene‐2‐(4‐oxoquinazolin‐3(4H)‐yl)acetohydrazides (5), focusing on the modification of sub-stitution in the quinazolin‐4(3H)‐one moiety. The biological evaluation showed thatall 13 designed and synthesized compounds displayed significant cytotoxicity againstthree human cancer cell lines (SW620, colon cancer; PC‐3, prostate cancer; NCI‐H23, lung cancer). The most potent compound5ldisplayed cytotoxicity up to 213‐fold more potent than 5‐fluorouracil and 87‐fold more potent than PAC‐1, the firstprocaspase‐activating compound. Structure–activity relationship analysis revealedthat substitution of either electron‐withdrawing or electron‐releasing groups atpositions 6 or 7 on the quinazolin‐4(3H)‐4‐one moiety increased the cytotoxicity ofthe compounds, but substitution at position 6 seemed to be more favorable. In thecaspase activation assay, compound5lwas found to activate the caspase activity by291% in comparison to PAC‐1, which was used as a control. Further docking si-mulation also revealed that this compound may be a potent allosteric inhibitor ofprocaspase‐3 through chelation of the inhibitory zinc ion. Physicochemical andADMET calculations for5lprovided useful information of its suitable absorptionprofile and some toxicological effects that need further optimization to be devel-oped as a promising anticancer agent