Utility of 3‐Formylchromone in the Synthesis of Polyfunctional Nitrogenous Hybrids: Empowered by Anticancer Efficiency and Molecular Simulations

ABSTRACT Chromone derivatives are integral platforms of various medicinal agents and natural products. This study successfully presents a facile approach for the regioselective synthesis of diversely substituted binary β ‐hydroxy ketones and fused chromone scaffolds. These targets were achieved through direct treatment of 4‐oxo‐4 H ‐chromene‐3‐carbaldehyde as a starting material with various heterocyclic systems and nucleophilic nitrogenous surrogates under mild conditions. Additionally, the utilized methodology demonstrated a broad substrate scope and good tolerance to various functionalities, utilizing ethanol as a top‐tier green solvent. The cytotoxic profile of the synthesized hybrids against MCF‐7 and HepG2 cell lines was debated, empowered by their DFT calculations and assessed drug‐likeness analysis using Lipinski and Ghose filters. Interestingly, all synthesized hybrids adhered to the key physicochemical parameters of both Lipinski's and Ghose's rules, with zero violations. Generally, the results showed that the tested hybrids are more active against the MCF‐7 cell line than the HepG2 cell line. Notably, compounds fused dihydropyrido[1,2,4]triazepine 11 and benzo[ d ]thiazole‐6‐sulfonamide 18 were the most effective compounds for MCF‐7 (IC 50 = 3.96 and 7.67 μg/mL), whereby tetracyclic compounds dihydropyrido[1,2‐ b ][1,2,4]triazepine 11 and N ‐(pyridin‐2‐yl)hydrazine‐1‐carbothioamide 18 were the most effective on HepG2 (IC 50 = 10.30 and 13.20 μg/mL) compared to cis ‐platin as standard drug (IC 50 = 8.60 on MCF‐7 and 9.08 μg/mL on HepG2).