1,5-Diarylpyrazole and vanillin hybrids: Synthesis, biological activity and DFT studies

• Published in: European journal of medicinal chemistry Vol. 100; pp. 106 - 118
• Main Authors: Hernández-Vázquez, Eduardo, Castañeda-Arriaga, Romina, Ramírez-Espinosa, Juan José, Medina-Campos, Omar Noel, Hernández-Luis, Francisco, Chaverri, José Pedraza, Estrada-Soto, Samuel
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.07.2015; Elsevier
• Subjects: Animals; Antioxidant capacity; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Benzaldehydes - chemistry; Benzaldehydes - pharmacology; Chemistry, Medicinal; DFT calculations; Diabetes Mellitus, Experimental - drug therapy; Diarylpyrazole hybrids; Dose-Response Relationship, Drug; Hypoglycemia - drug therapy; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Life Sciences & Biomedicine; Molecular Structure; Oxidative Stress - drug effects; Pharmacology & Pharmacy; Pyrazoles - chemistry; Pyrazoles - pharmacology; Quantum Theory; Rats; Science & Technology; Structure-Activity Relationship; Vanillin; Antioxidant capacity; Vanillin; DFT calculations; Diarylpyrazole hybrids; OXIDATIVE STRESS; GUAIACOL DERIVATIVES; VITAMIN-E; ACTIVATION; HYDROGEN-ATOM ABSTRACTION; RECEPTOR; MECHANISMS; DIABETES-MELLITUS; KINETICS; COMPLICATIONS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.06.010

Herein, we report the design and synthesis of 13 diarylpyrazole hybrids with vanillin constructed as dual compounds against oxidative stress and diabetes. Compounds were tested in two different antioxidant assays. It was found that all compounds showed an important antioxidant activity in both DPPH and ORAC models and the activity was even more remarkable than vanillin. In addition, the hypoglycemic effect of compounds 1, 2, 4 and 12 was evaluated. Interestingly, compound 1 had the most potent hypoglycemic effect with a glycemia reduction of 71%, which was higher than rimonabant. Finally, a DFT study to propose a reasonable antioxidant mechanism is detailed. Both thermodynamic and kinetic studies indicated that the most feasible mechanism consists in the HAT abstraction of the phenolic hydrogen due to the formation of an stable transition state through the most rapid and exergonic path, while the SPLET mechanism is the most significant at higher pH values. [Display omitted] •Pyrazole derivatives were designed and synthesized against oxidative stress and diabetes.•Compounds showed moderate antioxidant activity in both DPPH and ORAC assays.•Analogs tested had an important hypoglycemic reduction, which was higher than rimonabant.•DFT calculations proposed that both HAT and SPLET are involved in antioxidant activity.