Design, Synthesis, Molecular Modeling and Biological Evaluation of Novel Pyrazole Benzimidazolone Derivatives as Potent Antioxidants

Mohamed Adardour; Marouane Ait Lahcen; Mehdi Oubahmane; Walid Ettahiri; Ismail Hdoufane; Hafida Bouamama; Mohammed M Alanazi; Driss Cherqaoui; Mustapha Taleb; Elena Zaballos Garcia; Abdesselam Baouid

doi:10.3390/ph16121648

Design, Synthesis, Molecular Modeling and Biological Evaluation of Novel Pyrazole Benzimidazolone Derivatives as Potent Antioxidants

Pharmaceuticals (Basel). 2023 Nov 24;16(12):1648. doi: 10.3390/ph16121648.

Authors

Affiliations

¹ Molecular Chemistry Laboratory, Department of Chemistry, Semlalia Faculty of Sciences, 2390, Cadi Ayyad University, Marrakech 40001, Morocco.
² Laboratory of Engineering, Electrochemistry, Modeling and Environment, Faculty of Sciences, Sidi Mohamed Ben Abdellah University, Fez 30000, Morocco.
³ Laboratory of Sustainable Development and Health Research, Faculty of Sciences and Techniques, Cadi Ayyad University, Marrakech 40000, Morocco.
⁴ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
⁵ Sustainable Materials Research Center (SUSMAT-RC), University of Mohammed VI Polytechnic, Benguerir 43150, Morocco.
⁶ Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Ave. Vte. Andres Estelles s/n, 46100 Valencia, Spain.

Abstract

In the present study, we used benzimidazolone as a starting material to efficiently synthesize several hybrid compounds of pyrazole benzimidazolone derivatives by the 1,3-dipolar cycloaddition reaction. These compounds were obtained in average yields and were characterized by NMR (¹H and ¹³C) and HRMS analysis. The antioxidant activity of the synthesized compounds 5(a-c) and 6(a-c) was evaluated using in vitro reduction assays, including ferric reducing antioxidant power (FRAP) and total antioxidant capacity (TAC). The results indicated that products 5c, 6b, and 6c exhibit higher antioxidant activity compared to the reference compounds and showed a remarkable ability to effectively remove the radical at IC₅₀ (14.00 ± 0.14, 12.47± 0.02, and 12.82 ± 0.10 µM, respectively) under the TAC assessment. Conversely, compound 6c showed excellent activity at IC₅₀ (68.97 ± 0.26 µM) in the FRAP assay. We carried out molecular docking and dynamics simulations to investigate the binding mode and stability of 5c, 6b, and 6c in the active site of human Peroxiredoxin 5. An ADMET study was conducted to determine the drug properties of the synthesized compounds.

Keywords: FRAP; TAC; antioxidant activity; molecular docking; pyrazolyl-benzimidazolone.

Grants and funding

The authors extend their appreciation to the Researchers Supporting Project number (RSPD2023R628), King Saud University, Riyadh, Saudi Arabia, for supporting this research.