Synthesis of Novel Hybrid Heterocycles Tethered 2,3‐Diphenoxyquinoxaline Moiety via Hantzsch, Michael, and Biginelli Reactions: Antimicrobial Activities and Molecular Docking Simulation

In this study, we have developed new hybrid compounds by connecting bis‐heterocycles with a 2,3‐diphenoxyquinoxaline core. This is performed by combining 4,4′‐(quinoxaline‐2,3‐diylbis(oxy))dibenzaldehyde with the necessary reagents via Hantzsch and Biginelli reactions. The newly synthesized compounds' structures are determined by elemental analysis, 1 H NMR, 13 C NMR, IR, and MS spectra. The tested compound 18 has the strongest antibacterial activities against S. aureus and E. coli , with inhibition zones of 18 and 14.67 mm, respectively. The tested compound 5 exhibited the strongest antibacterial activities against S. aureus , with an inhibition zone of 17 mm. Molecular docking studies of the most efficient compounds were performed against two proteins, including ATP‐dependent Clp protease ATP‐binding subunit ClpA (UniProt ID: P0ABH9) and Glycerol dehydrogenase (GDH) (UniProt ID: P0A9S5). Compound 5 interacted with the ClpA active site, exhibiting a binding score of ∆G = −9.2 Kcal/mol, while 18 interacted with the GDH active site, exhibiting a binding score of ∆G = −11.4 Kcal/mol.