Exploring the chemical reactivity of 2,6-dimethylchromone toward heterocyclic hydrazines and enamines: experimental and theoretical investigations.

The current study aimed to investigate the chemical behavior of 2,6-dimethylchromone (1) towards some heterocyclic hydrazines and cyclic enamines. Reaction of compound 1 with 7-chloro-4-hydrazinylquinoline and 3-hydrazinyl-5,6-diphenyl-1,2,4-triazine gave pyrazole derivatives 4 and 5. Treatment of compound 1 with 5-amino-3-methyl-1-pyrazole, 6-aminouracil, 6-aminothiouracil and 1,3-dimethyl-6-aminouracil produced pyrazolo[3,4-]pyridine 6 and pyrido[2,3-]pyrimidines 7-9, respectively. The biological efficiency of the synthesized compounds against hepatocellular carcinoma (HepG-2) cell lines was investigated through a combination of experimental and theoretical approaches, including molecular docking with the CDK1 protein (PDB ID: 4Y72). Among the tested molecules, compound 5 exhibited the most potent anticancer activity, with an IC value of 6.57 µM L, surpassing the reference drug . For theoretical studies, all compounds were geometrically optimized using DFT/B3LYP functional with the 6-311G++(d,p) basis set. Structural parameters and global reactivity descriptors were calculated to predict the compounds' chemical reactivity and kinetic stability. Molecular Electrostatic Potential (MEP) surfaces were employed to visualize charge distribution and identify potential reactive sites within the molecules. Likewise, simulated infrared (IR) and NMR spectra from DFT calculations were consistent with their experimental counterparts. Additionally, experimental infrared (IR) and nuclear magnetic resonance (NMR) spectra were compared with their corresponding simulated spectra derived from DFT calculations, demonstrating strong consistency. In addition, the non-linear optical (NLO) properties of the compounds were assessed and found to exceed those of urea, a standard reference compound. SwissADME analysis was also performed to evaluate the pharmacokinetic profiles and drug-likeness of the synthesized molecules. Finally, molecular docking studies targeting cyclin-dependent kinases CDK1 (PDB ID: 4Y72) were conducted to explore the binding interactions of the synthesized compounds. The docking results showed a strong correlation with their observed anticancer activities, supporting that these compounds are promising candidates for HepG-2 cell lines.