Synthesis of pyrazole and pyrazoline derivatives of β-ionone: Exploring anti-inflammatory potential, cytotoxicity, and molecular docking insights

In the present paper, pyrazole and pyrazoline derivatives of β-ionone were synthesized. The protocol involved intramolecular oxidative C–H amination of hydrazone to yield corresponding pyrazole in moderate to good yields. Another methodology comprising of condensation of hydrazine hydrochloride with β-ionone in methanol leading to pyrazoline and its oxidative dehydrogenation using hypervalent iodine reagent to synthesize pyrazole is also achieved. One pot methodology for synthesis of pyrazole is also developed by refluxing the hydrazine hydrochloride with β-ionone in acetic acid. The structures of the synthesized compounds were elucidated using 1 H NMR, 13 C NMR, FTIR and mass spectrometry. All the pyrazole and pyrazoline derivatives were subjected to bovine serum albumin assay for in-vitro anti-inflammatory activity and all the compounds exhibited good to excellent activity. Compounds containing bromo and sulfonamide group exhibited inhibition rates of 87.36 % and 85.82 %, respectively, at a concentration of 0.5 mg/mL, surpassing the efficacy of the standard drug celecoxib (81.67 %). Further, cytotoxicity of the compounds was also evaluated against VERO cell line and all the compounds exhibited the cytotoxic values almost similar to the standard. Molecular docking was performed to study binding affinity of the potent compounds i. e bromo bearing pyrazole and sulfonamide bearing pyrazoline into the crystal structure of COX-II enzyme (PDB ID: 3LN1 ) at celecoxib binding site to determine the binding energy and interactions. • Synthesis of pyrazole by oxidative cyclization of hydrazone derivatives using PIFA in HFIP. • One pot synthesis of pyrazole and pyrazoline by refluxing β-ionone with derivatives of phenyl hydrazine hydrochloride in glacial acetic acid and methanol respectively. • Pyrazole bearing bromo ( 4h ) and pyrazoline bearing sulfonamide ( 6g ) showed superior in-vitro anti-inflammatory activity than celecoxib. • Cytotoxicity studies were carried out against VERO cell line using colorimetric assay and results indicated similar values of cytotoxicity as standard. • The molecular docking with the COX-II enzyme revealed that 4h exhibited more negative value of binding energy compared to 6g.