Bioactivity of novel isoxazole-fused heterocycles: comprehensive antimicrobial, antioxidant activities, SwissADME predictions, molecular docking, and DFT analysis

Abstract Among the foremost goals for organic chemists is to discover novel approaches for the synthesis of a particular heterocyclic and its design. Our approach focused on the vital precursor 4-acetyl-3-phenylisoxazol-5(4 H )-one 3 , as this molecule has an endocyclic carbonyl function in position 5 adjacent to the substituted acetyl function at site 4. Therefore, compound 3 was a crucial component of many types of fused isoxazole. The investigators provide a straightforward synthesis of fused isoxazole from the following categories: pyrano[3,2- d ]isoxazole 4 & 6 , isochromeno[4,3- d ]isoxazole 5 , isoxazolo[4',5':5,6]pyrano[3,4- c ]pyridine 7 , thieno[3',4':4,5]pyrano [3,2- d ]isoxazole 8 , pyrazolo[4,3- d ]isoxazole 10a,b and 11a,b , and isoxazolo[4,5- c ]pyridazine derivatives 14a,b . The target compounds and their structures were supported by the results of 1 H-NMR, IR and mass spectroscopy. Molecular docking studies highlighted strong binding affinities to bacterial enzymes crucial for cell wall synthesis, while DFT calculations provided deep insights into their electronic properties and stability. Additionally, the antioxidant potential of compounds 11a,b was assessed using DPPH and ABTS assays, showing impressive concentration-dependent activity. Addressing the critical issue of antibiotic resistance, especially due to β-lactamases, molecular docking affirmed the high binding propensity of these derivatives with essential β-lactamase proteins (PDB: 1CK3, 6MU9, and 6W2Z). These findings underscore the promise of isoxazoline derivatives as powerful antimicrobial and antioxidant agents, paving the way for further development in combating bacterial resistance and oxidative stress.