Synthetic approaches for novel 3-heteroaryl-4-hydroxy-1-methylquinoline-2(1H)one: spectroscopic characterization, molecular docking and DFT investigations

Abstract

Ring opening and recyclization reactions with 4-hydroxy-6-methyl-3-nitro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (1) was examined towards some carbon nucleophilic reagents. Treatment of key precursor 1 with cyanoacetamide, malononitrile dimer and 1H-benzimidazol-2-ylacetonitrile afforded pyridines 2, 3 and pyrido[1,2-a]benzimidazole 4, respectively. Reaction of compound 1 with 5-amino-2,4-dihydro-3H-pyrazol-3-one and 5-amino-3-methyl-1H-pyrazole furnished pyrazolo[3,4-b]pyridine derivatives 5 and 6. Further, pyrido[2,3-d]pyrimidines 7–9 were synthesized from recyclization of compound 1 with some 6-aminouracil derivatives. Compounds 2–4 demonstrated favorable efficacy in HepG-2 liver cancer cells comparable to reference drug (cisplatin), exhibiting IC₅₀ values of 8.79–17.78 μM L⁻¹. The optimized geometrical configurations of the synthesized compounds were determined, using DFT calculations conducted at the B3LYP/6-311++G(d,p) level, for computing various parameters including molecular electrostatic potential (MEP), global reactivity indices, frontier molecular orbital (FMO) analysis, and nonlinear optical (NLO) characteristics. The obtained results revealed that, compound 3 exhibits the smallest energy gap (ΔE = 2.783 eV), while compound 9 presents the largest energy gap (ΔE = 3.995 eV). Also, compound 9 with a hardness value (η) of 1.998 eV demonstrated greater hardness and stability compared to other compounds, whereas compound 3 with a softness value (S) of 0.719 eV⁻¹, is comparatively softer and more reactive. The experimental infrared (IR) and nuclear magnetic resonance (NMR) spectra of the current compounds were compared with the simulated spectra derived from DFT computations, revealing a good agreement. SwissADME analyses suggested that all prepared compounds adhere to the Lipinski, Ghose, and Veber principles fitting to drug likeness. Utilizing the topoisomerase IIβ protein (PDB ID: 4G0U) as a receptor, molecular docking analyses were conducted to investigate the binding interactions of the synthesized compounds and correlated with their anticancer efficacy. Further, MEP surfaces of the studied compounds were analyzed to ascertain the reactive sites appropriated to electrophilic and nucleophilic attacks. The theoretical investigation suggests that the synthesized compounds possess potential applicability for future NLO applications.