Flavonoid Derivatives as Potential Cholinesterase Inhibitors in Scopolamine-Induced Amnesic Mice: An In Vitro, In Vivo and Integrated Computational Approach

Fakhria A Al-Joufi; Syed Wadood Ali Shah; Mohammad Shoaib; Mehreen Ghias; Shafiullah; Atif Ali Khan Khalil; Syed Babar Jamal; Syed Muhammad Hassan Shah; Muhammad Zahoor

doi:10.3390/brainsci12060731

Flavonoid Derivatives as Potential Cholinesterase Inhibitors in Scopolamine-Induced Amnesic Mice: An In Vitro, In Vivo and Integrated Computational Approach

Brain Sci. 2022 Jun 2;12(6):731. doi: 10.3390/brainsci12060731.

Authors

Fakhria A Al-Joufi¹, Syed Wadood Ali Shah², Mohammad Shoaib², Mehreen Ghias², Shafiullah², Atif Ali Khan Khalil³, Syed Babar Jamal³, Syed Muhammad Hassan Shah⁴, Muhammad Zahoor⁵

Affiliations

¹ Department of Pharmacology, College of Pharmacy, Jouf University, Skaka 72341, Aljouf, Saudi Arabia.
² Department of Pharmacy, University of Malakand, Dir (Lower), Chakdara 18800, Khyber Pakhtunkhwa, Pakistan.
³ Department of Biological Sciences, National University of Medical Sciences, Rawalpindi 46000, Punjab, Pakistan.
⁴ Department of Pharmacy, Sarhad University of Science and Information Technology, Peshawar 25000, Khyber Pakhtunkhwa, Pakistan.
⁵ Department of Biochemistry, University of Malakand, Dir (Lower), Chakdara 18800, Khyber Pakhtunkhwa, Pakistan.

Abstract

Flavonoids are one of the most exciting types of phenolic compounds with a wide range of bioactive benefits. A series of flavone derivatives (F1-F5) were previously synthesized from substituted O-hydroxy acetophenone and substituted chloro-benzaldehydes. The titled compounds F1-F5 in the present study were evaluated for their anticholinesterase potential (against AChE and BuChE). The obtained results were then validated through a molecular docking approach. Compound F5 was found to be the most potent inhibitor of AChE (IC₅₀ = 98.42 ± 0.97 µg/mL) followed by compound F4, whereas compound F2 was found to be the most promising inhibitor of BuChE (IC₅₀ = 105.20 ± 1.43 µg/mL) among the tested compounds. The molecular docking analysis revealed a similar trend in the binding affinity of compounds with the targeted enzymes and found them to be capable of forming highly stable complexes with both receptors. The selected compounds were further subjected to in vivo assessment of cognitive function in a scopolamine-induced amnesic animal model, in which almost all compounds F1-F5 significantly attenuated the amnesic effects as evaluated through Y-Maze Paradigm and novel object discrimination (NOD) tasks, findings that were further supported by ex vivo experimental results. Among (F1-F5), F5 showed significant anti-amnesic effects in scopolamine-induced amnesic models and ameliorated the memory loss in behavioral model studies as compared to counterparts. In ex vivo study, noteworthy protection from oxidative stress in the brains of scopolamine-induced amnesic mice was also recorded for F5. These findings also confirmed that there were no significant differences among the in vivo and ex vivo results after administration of F1-F5 (7.5 or 15 mg/kg) or donepezil (2 mg/kg). These synthesized flavonoids could serve as potential candidates for new neuroprotective and nootropic drugs. However, further studies are needed to validate their observed potential in other animal models as well.

Keywords: AChE; Alzheimer’s disease; docking; enzyme inhibition; flavones; nootropic agents.

Grants and funding

This study was supported by the Higher Education Research Endowment Fund by Higher Education Department Khyber Pakhtunkhwa, Pakistan, grant number HEREF-50 and Saudi Arabia under the Research Groups Program.