Synthesis, Characterization, DFT Mechanistic Study, Antimicrobial Activity, Molecular Modeling, and ADMET Properties of Novel Pyrazole-isoxazoline Hybrids

Mohammed Chalkha; Hassan Nour; Khalid Chebbac; Asmae Nakkabi; Lahoucine Bahsis; Mohamed Bakhouch; Mohamed Akhazzane; Mohamed Bourass; Samir Chtita; Yousef A Bin Jardan; Maria Augustyniak; Mohammed Bourhia; Mourad A M Aboul-Soud; Mohamed El Yazidi

doi:10.1021/acsomega.2c05788

Synthesis, Characterization, DFT Mechanistic Study, Antimicrobial Activity, Molecular Modeling, and ADMET Properties of Novel Pyrazole-isoxazoline Hybrids

ACS Omega. 2022 Dec 8;7(50):46731-46744. doi: 10.1021/acsomega.2c05788. eCollection 2022 Dec 20.

Authors

Affiliations

¹ Engineering Laboratory of Organometallic, Molecular, Materials and Environment, Faculty of Sciences Dhar EL Mahraz, Sidi Mohamed Ben Abdellah University, P.O. Box 1796, 30000 Fez, Morocco.
² Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, P.O. Box 7955, Casablanca, Morocco.
³ Laboratory of Biotechnology Conservation and Valorisation of Natural Resources, Faculty of Sciences Dhar El Mahraz, Sidi Mohammed Ben Abdallah University, P.O. Box 1796, Fez 30000, Morocco.
⁴ Laboratory of Analytical and Molecular Chemistry, Polydisciplinary Faculty, Cadi Ayyad University, P.O. Box 4162, Safi 46000, Morocco.
⁵ Department of Chemistry, Faculty of Sciences of El Jadida, Chouaïb Doukkali University, P.O. Box 20, El Jadida 24000, Morocco.
⁶ Laboratory of Bioorganic Chemistry, Department of Chemistry, Faculty of Sciences, Chouaïb Doukkali University, P.O. Box 24, El Jadida 24000, Morocco.
⁷ Cité de l'innovation, Université Sidi Mohamed Ben Abdellah, Route Immouzer, P.O. Box 2626, 30000 Fez, Morocco.
⁸ Université de Bordeaux, CNRS, Bordeaux INP, ISM, UMR 5255, 351 Cours de la Libération, F-33405 Talence, Cédex France.
⁹ Department of Pharmaceutics, College of Pharmacy, King Saud University, 11451 Riyadh, Saudi Arabia.
¹⁰ Institute of Biology, Biotechnology and Environmental Protection, Faculty of Natural Sciences, University of Silesia in Katowice, Bankowa 9, 40-007 Katowice, Poland.
¹¹ Higher Institute of Nursing Professions and Technical Health, Laayoune 70000, Morocco.
¹² Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia.

Abstract

A series of new heterocycle hybrids incorporating pyrazole and isoxazoline rings was successfully synthesized, characterized, and evaluated for their antimicrobial responses. The synthesized compounds were obtained utilizing N-alkylation and 1,3-dipolar cycloaddition reactions, as well as their structures were established through spectroscopic methods and confirmed by mass spectrometry. To get more light on the regioselective synthesis of new hybrid compounds, mechanistic studies were performed using DFT calculations with B3LYP/6-31G(d,p) basis set. Additionally, the results of the preliminary screening indicate that some of the examined hybrids showed potent antimicrobial activity, compared to standard drugs. The results confirm that the antimicrobial activity is strongly dependent on the nature of the substituents linked pyrazole and isoxazoline rings. Furthermore, molecular docking studies were conducted to highlight the interaction modes between the investigated hybrid compounds and the Escherichia coli and Candida albicans receptors. Notably, the results demonstrate that the investigated compounds have strong protein binding affinities. The stability of the formed complexes by the binding between the hybrid compound 6c, and the target proteins was also confirmed using a 100 ns molecular dynamics simulation. Finally, the prediction of ADMET properties suggests that almost all hybrid compounds possess good pharmacokinetic profiles and no signs of observed toxicity, except for compounds 6e, 6f, and 6g.