A simple and efficient synthesis of a series of acetohydrazones (5a-l, 6a-l, 7a-l), 1,3-dioxoisoindolines (8a-c) derivatives and 1,2,4-triazole (9) have been attained starting from the key precursors acetohydrazides (4a-c). In addition, 1,2,4-triazole (9) have been employed for additional cyclization to afford [1,2,4]triazolo[3,4- b][1,3,4]thiadiazine derivatives (10a-c) as well as in synthesis of hydrazones (11a-f). Structures of the newly synthesized compounds have been confirmed by physical and spectral data (IR, 1H-NMR, M.S and 13C-NMR (APT)) in addition to elemental analysis. All the newly synthesized compounds were investigated for their in vivo antiinflammatory activity using the carrageenan-induced rat paw edema model. Most of the newly synthesized compounds demonstrated exceptionally high in vivo anti-inflammatory activity as compared to INM. The in vitro inhibitory activity of the most active compounds towards ovine cyclooxygenase COX-1 and human recombinant COX-2 was also assessed. All the bioactive compounds showed high affinity and selectivity towards COX-2 isozyme compared to the reference drug diclofenac sodium with IC50 values ranging from 0.28-0.81 μmole versus 0.80 μmole respectively. Molecular docking study was done and revealed a relationship between docking affinity and biological results.