A series of novel 2-methyl-5-[2-(substituted)phenyl]-1,3,4-oxadiazole derivatives (6a–6i) was synthesized via a multi-step protocol starting from commercially available salicylic acid (1). The initial esterification of salicylic acid using thionyl chloride and ethanol at 80 °C for 12 h yielded ethyl 2-hydroxybenzoate (2), which was subsequently converted to 2-hydroxybenzohydrazide (3) upon treatment with hydrazine monohydrate in ethanol at 80 °C for 2 h. Acetylation of intermediate 3 with acetic anhydride afforded N’-acetyl-2-hydroxybenzoate (4), which was reacted with various halo compounds (4a–4i) to produce a series of N’-acetyl-2-(substituted)oxybenzohydrazides (5a–5i). These key intermediates were cyclized using triphenylphosphine, triethylamine, carbon tetrachloride, and acetonitrile at 100 °C for 1 h to furnish the final oxadiazole derivatives (6a–6i). The compounds were purified using appropriate chromatographic techniques and fully characterized by 1H NMR, 13C NMR, FTIR, and mass spectrometry. Biological screening of the synthesized compounds revealed that several derivatives, particularly 6c, 6d, and 6g, exhibited promising antimicrobial and antioxidant activities. Notably, compound 6a demonstrated significant cytotoxicity against HeLa cancer cells. Molecular docking studies further supported the biological potential of the compounds, with 6e displaying a high docking score of –5.66 kcal/mol.
