Abstract
Isatin derivatives potentially act on various biological targets. In this article, a series of novel isatin-hydrazones were synthesized in excellent yields. Their cytotoxicity was tested against human breast adenocarcinoma (MCF7) and human ovary adenocarcinoma (A2780) cell lines using MTT assay. Compounds 4j (IC50 = 1.51 ± 0.09 µM) and 4k (IC50 = 3.56 ± 0.31) showed excellent activity against MCF7, whereas compound 4e showed considerable cytotoxicity against both tested cell lines, MCF7 (IC50 = 5.46 ± 0.71 µM) and A2780 (IC50 = 18.96± 2.52 µM), respectively. Structure-activity relationships (SARs) revealed that, halogen substituents at 2,6-position of the C-ring of isatin-hydrazones are the most potent derivatives. In-silico absorption, distribution, metabolism and excretion (ADME) results demonstrated recommended drug likeness properties. Compounds 4j (IC50 = 0.245 µM) and 4k (IC50 = 0.300 µM) exhibited good inhibitory activity against the cell cycle regulator CDK2 protein kinase compared to imatinib (IC50 = 0.131 µM). A molecular docking study of 4j and 4k confirmed both compounds as type II ATP competitive inhibitors that made interactions with ATP binding pocket residues, as well as lacking interactions with active state DFG motif residues.
Highlights
Development of anticancer drugs is essential due to the increasing number of morbidity and mortality by cancer day-by-day all over the world
Considering the importance of the development of anticancer therapeutics and the various biological properties of isatin and isatin nucleus-containing derivatives, a series of isatin-hydrazones were designed and synthesized, their cytotoxicities against two different cancer cell lines, namely MCF7 and A2780, were evaluated, their structure–activity relationships (SARs) were studied, their ADME properties were studied using in silico ADME tools and cyclin-dependent kinases 2 inhibitory activities were performed using an enzyme inhibition assay
A mixture of isatin (1) and hydrazine hydrate was refluxed in ethanol and isatin monohydrazone (2) was obtained in quantitative yields (~99%)
Summary
Development of anticancer drugs is essential due to the increasing number of morbidity and mortality by cancer day-by-day all over the world. Molecules 2020, 25, 4400 high specificity becomes imperative To overcome these challenges, researchers should develop a drug molecule with potent biological activity and low/no toxicity, study its mode of action, in silico properties and in vitro/vivo metabolism, conduct a toxicity evaluation [4,5], study its topoisomerase inhibitory activity [6,7,8] and enzyme inhibitory activity [9], etc., all of which are some of the key evaluation practices for the development of potential anticancer therapeutics. Considering the importance of the development of anticancer therapeutics and the various biological properties of isatin and isatin nucleus-containing derivatives, a series of isatin-hydrazones were designed and synthesized, their cytotoxicities against two different cancer cell lines, namely MCF7 (human breast adenocarcinoma) and A2780 (human ovary adenocarcinoma), were evaluated, their structure–activity relationships (SARs) were studied, their ADME properties were studied using in silico ADME tools and cyclin-dependent kinases 2 inhibitory activities were performed using an enzyme inhibition assay. Docking simulations were conducted in order to explore the behavior of the synthesized compounds within the active site of CDK2 to justify its binding mechanism
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