Synthesis, in vitro antimicrobial activity and docking studies of novel 1,2,4-oxadiazole based...

A set of novel 1,2,4-oxadiazol based piperidin-1-yl-methanone analogues (5a-k) was synthesized from 3-phenyl-5-(4-(piperidin-4-yl)phenyl)-1,2,4-oxadiazole (3) via a sequential hydrolysis, cyclization and the Schotten-Baumann reaction. The structures of synthesized compounds were characterized using ¹H NMR, ¹³C NMR and mass spectrometry data. Moreover, all compounds were evaluated for their preliminary antimicrobial activity against Gram-negative, Gram-positive bacterial, as well as fungal pathogens, employing the disk diffusion method. Most of the evaluated compounds displayed exceptional antimicrobial activity, when compared with standard Ampicillin, Griseofulvin. Notably, compounds 5b, 5e, 5i, 5j and 5k exhibited significant anti-bacterial activity, with zone of inhibition of 20-25 mm at 50 μg/ml and MIC values ranging from 1.6-2.2 μg/mL. The antifungal activity revealed MIC values in the range of 1.7-1.9 μg/mL. Molecular docking studies were conducted against penicillin-binding protein (PBP, PDB ID: 3TTZ), a key enzyme involved in bacterial cell wall biosynthesis. The synthesized compounds exhibited favorable binding interactions within the active site of PBP through H-bonds and hydrophobic interactions, supported by stable binding energies, with crucial residues. These results suggest that the developed 1,2,4-oxadiazol based piperidin-1-yl-methanone analogues favorable stability, have potential as effective antibacterial agents against targeting PBP inhibition.