Heterocyclic coumarin derivatives as anti-oxidant agents and cytotoxic inducers in lung cancer cell lines
March 26, 2026
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| Article Title: | Heterocyclic coumarin derivatives as anti-oxidant agents and cytotoxic inducers in lung cancer cell lines |
| Authors: | Mahdi A.G., Raheem L.A.R. |
| Affiliation: | Department of Pharmaceutical Chemistry, College of Pharmacy, University of Basrah |
| Abstract: | Compounds with a coumarin function are widely distributed in nature and have potential application as anticancer and antioxidant agents. Compounds that exhibit dual antioxidant and selective cytotoxicity towards malignant cells with relatively low toxicity towards normal tissues are of great interest in medicinal chemistry. As per global cancer statistics, lung cancer is the worst cancer regarding mortality rates. To ease this global burden, lung cancer requires novel lung cancer therapies. Specifically, therapies that target multiple pathways simultaneously. The primary aim of this research work is systemic study of synthesis, characterization, antioxidant activity and cytotoxicity of novel heterocyclic coumarin derivatives especially 7-hydroxy-4-methylcoumarin derivatives against human lung adenocarcinoma cell-lines. The research’s objective is to understand structure-activity relationships and molecular mechanisms of action using computational modelling approaches. What was done: A library of 15 heterocyclic coumarin derivatives was synthesized through reuseable solid-acid catalysed environmentally friendly Pechmann condensation. The antioxidant activity was carried out with more than one validated method like DPPH and ABTS radical scavenging assays, ferric reducing antioxidant power (FRAP), etc. Cytotoxicity was assessed using an MTT colorimetric assay in A549 human lung adenocarcinoma and MRC-5 normal human lung fibroblast cell lines using a complete dose response assay. Molecular docking studies were done using AutoDock Vina to study the binding mechanism with some key cancer-related proteins such as cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and tumor suppressor p53. The synthesized compounds were found to show excellent antioxidant activity with IC₅₀ ranging from 4.2 to 15.8 μM and strong cytotoxic effect on A549 cells (IC₅₀ = 4.48-12.5 μM). The most promising biological profile belonged to compound 11g featuring pyrazole heterocycle and an IC50 of 4.48 ± 0.57 μM against A549. It was more potent than the reference drug celecoxib (7.68 ± 0.55 μM). With a selectivity index of 3.8, it has a preference towards tumor cells. Through a comprehensive structure-activity relationship analysis, we found that the biological activity for the 7-hydroxy-4-methylcoumarin core is necessary, and the heterocyclic substitution enhances its activity in the following order: pyrazole > thiazole > triazole. Molecular docking studies provided mechanistic insights, which showed good binding affinities to COX-2 (-9.2 kcal/mol) and 5-LOX (-8.7 kcal/mol). The docking analysis showed that the compound might bind to 5-LOX and COX-2 through various intermolecular interactions. In conclusion, Heterocyclic coumarin derivatives, especially pyrazole-coumarin hybrids, are a highly promising dual antioxidant-anticancer therapeutic for the treatment of lung cancer with a better selectivity and lesser chance of systemic toxicity. Using the established synthetic methodology, a variety of analogs can be produced sustainably. In addition, the complete biological evaluation leads to lead compounds for further preclinical development. |
| Keywords: | coumarin derivatives, 7-hydroxy-4-methylcoumarin, heterocyclic compounds, green chemistry, lung cancer therapeutics. |
| *Correspondence: | Ali Ghanem Mahdi, Department of Pharmaceutical Chemistry, College of Pharmacy, University of Basrah, email: hsennaserh@yahoo.com |
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