Ligand-free palladium-catalyzed synthesis of 3-(2,2-dialkyl-2H-chromen-4-yl)-2-phenylimidazo[1,2-a]pyridine derivatives: molecular docking investigation of their potential as DNA gyrase inhibitors and evaluation of their antibacterial activities†

Abstract

Palladium-catalyzed reactions between imidazo[1,2-a]pyridine derivatives and 4-bromo-2,2-dialkyl-substituted 2H-chromenes under microwave irradiation at 100 W, 120 °C for 20–30 min provided a series of new 3-(2,2-dialkyl-2H-chromen-4-yl)-2-phenylimidazo[1,2-a]pyridine derivatives in good to excellent yields. The structures of the synthesized compounds were confirmed through spectroscopic techniques (NMR and HRMS). The X-ray single-crystal structure of compound 16e was also determined. Shorter reaction time, high yield and good substrate scope were the major advantages of this method. All these compounds were further investigated in vitro for the evaluation of their antibacterial potency using the agar well diffusion method against human pathogenic Gram-negative E. coli and Gram-positive S. aureus bacteria, with the determination of their minimum inhibitory concentration (MIC) values. Indeed, compound 16h strongly inhibited DNA gyrase in silico with a binding affinity of −8.7 kcal mol⁻¹ and exhibited zone of inhibition (ZI) values of 19 mm and MIC values of 10 μg mL⁻¹ in both Gram-negative E. coli and Gram-positive S. aureus, relative to the standard drug gentamicin. By analyzing the structure–activity relationships based on the molecular docking results and the potent antibacterial activities, it could be concluded that these new phenylimidazo[1,2-a]pyridine-chromene derivatives have the potential to be effective druggable antibacterial agents.