New Imidazole-Based N-Phenylbenzamide Derivatives as Potential Anticancer Agents: Key Computational Insights

M Shaheer Malik; Reem I Alsantali; Qazi Mohammad Sajid Jamal; Zaki S Seddigi; Moataz Morad; Meshari A Alsharif; Essam M Hussein; Rabab S Jassas; Munirah M Al-Rooqi; Zainularifeen Abduljaleel; Ahmed O Babalgith; Hatem M Altass; Ziad Moussa; Saleh A Ahmed

doi:10.3389/fchem.2021.808556

New Imidazole-Based N-Phenylbenzamide Derivatives as Potential Anticancer Agents: Key Computational Insights

Front Chem. 2022 Jan 19:9:808556. doi: 10.3389/fchem.2021.808556. eCollection 2021.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University, Makkah, Saudi Arabia.
² Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia.
³ Department of Health Informatics, College of Public Health and Health Informatics, Qassim University, Al Bukayriyah, Saudi Arabia.
⁴ Department of Environmental Health, College of Public Health and Health Informatics, Umm Al-Qura University, Makkah, Saudi Arabia.
⁵ Department of Chemistry, Faculty of Science, Assiut University, Assiut, Egypt.
⁶ Department of Chemistry, Jamoum University College, Umm Al-Qura University, Makkah, Saudi Arabia.
⁷ Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.
⁸ Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
⁹ Department of Chemistry, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.

Abstract

An efficient atom-economical synthetic protocol to access new imidazole-based N-phenylbenzamide derivatives is described. A one-pot three-component reaction was utilized to provide a series of N-phenylbenzamide derivatives in a short reaction time (2-4 h) with an 80-85% yield. The cytotoxic evaluation revealed that derivatives 4e and 4f exhibited good activity, with IC₅₀ values between 7.5 and 11.1 μM against the tested cancer cell lines. Computational studies revealed interesting insights: the docking of the active derivatives (4e and 4f) showed a higher affinity toward the target receptor protein than the control. Molecular dynamic simulations revealed that the active derivatives form stable complexes with the ABL1 kinase protein. Moreover, the ADME and drug-likeness of the derivatives reinforced the potential of the derivatives to be taken up for further development as anticancer agents.

Keywords: ADME and drug-likeness; N-phenylbenzamide; anticancer activity; computational studies; imidazole; molecular dynamic simulations; multicomponent reaction.