C(3)–H alkenylation of quinoxalin-2(1H)-ones with Hantzsch esters and in silico studies

Abstract

A novel and efficient method for the C(3)–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 with yields ranging from good to high. The scope of the reaction was demonstrated by synthesizing 36 examples of quinoxalinone–pyridines in yields ranging from 61% to 82%. Quinoxalinone ring-containing drugs are well known for different pharmaceutical activities and, therefore, in the present case, we conducted a thorough in silico screening of the synthesized molecules (3a–3e′) to elucidate their potent biological activities. We have adopted standard computational protocols, including DFT calculations, ADMET analysis, pharmacophore mapping, and molecular docking with proteins, to study the optimized geometries of the synthesized ligands. Protein scaffolds associated with cancer, diabetes, inflammation, and antimicrobial activity were targeted to investigate the drug likeness. The method revealed that compounds 3h–3m, among the 31 molecules, show high potential as viable drugs. Specifically, 3l yielded the best docking result, and the MD simulation indicated that 3l has potential as a drug candidate.