Design, synthesis, in-vitro and in-silico studies of chromone-isoxazoline conjugates as anti-bacterial agents

A novel series of chromone-isoxazoline conjugates was successfully synthesized by the O-alkylation and 1,3dipolar cycloaddition reactions using methyl 7-hydroxy-4H-chromone-3-carboxylate as starting material. The structures of the synthesized hybrid compounds were determined using spectroscopic techniques, and mass spectrometry. The in-vitro antibacterial activity of the target compounds was tested against four bacterial strains, and it was found that compound 5e was active against the strains B. subtilis and P. mirabilis. Theoretical calculations were made at the B3LYP, HF, and M062X level on a 6-31++g(d,p) basis in order to optimize the geometric structures and calculate the geometric and electronic structure parameters of the target compounds. In addition, molecular docking studies were performed to understand and identify the mode of interaction between the hybrid compound 5e and the bacterial proteins of B. subtilis and P. mirabilis. The outcomes revealed that the hybrid compound 5e displayed strong binding affinities within the target receptors' active site. Also, a 100 ns molecular dynamics simulation was used to assess the behavior and stability of the complexes formed between ligand 5e and the bacterial receptors. Lastly, in silico ADMET analyses suggest that the target compounds exhibit favorable pharmacokinetic properties, including significant oral bioavailability.