Convergent synthesis of quinoxalinone-pyridine scaffolds via C3-H alkenylation of quinoxalin-2(1H)-ones with Hantzsch esters and its in-silico studies

Abstract

A novel and efficient method for the C3-H alkenylation of quinoxalin-2(1H)-ones has been developed using trifluoroacetic acid (TFA) as a Brønsted acid catalyst and Hantzsch esters (HEs) as the alkenylating agent. This metal-free protocol provides direct access to structurally diverse quinoxalinone-pyridine hybrid scaffolds under mild conditions, offering excellent functional group tolerance in yields ranging from good to high. During the overall transformation, new carbon-carbon double bonds were introduced in the products. The scope of the reaction was demonstrated by synthesizing 36 examples of quinoxalinone-pyridines in 61-82% yields. A number of synthesized molecules (3a -3e') were thoroughly screened through in silico methods to elucidate their potent biological activities. DFT calculations were performed for all molecules to assess their stability and reactivity via the geometry optimization, along with other global properties, such as the HOMO-LUMO energy gaps, chemical potentials, Ionization potentials, electronegativities, electron affinities, and dipole moments. The optimized geometries were utilized for further in silico screening through ADMET analysis, pharmacophore mapping, and molecular docking with proteins associated with cancer, diabetes, inflammation, and antimicrobial activity. This screening revealed that compounds 3h -3m, among the 31 molecules, show high affinity and potential to be viable drugs, and specifically, 3l yielded the best docking result. MD simulation confirms the stability and effective binding of the ligand to active sites of the proteins (4UND for anticancer and 2PRG for anti-diabetic). Additionally, MM/PBSA analysis further validated the results, which show high binding affinity towards these proteins, confirming the potential of 3l to be a lead molecule as a drug.