Flavonoids as acetylcholinesterase inhibitors: Current therapeutic standing and future prospects.

Biomed Pharmacother. 2018 May;101:860-870. doi: 10.1016/j.biopha.2018.03.007. Epub 2018 Mar 22. Khan H1, Marya2, Amin S3, Kamal MA4, Patel S5. Author information 1 Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan. Electronic address: haroonkhan@awkum.edu.pk. 2 Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan. 3 Department of Botany, Islamia College Peshawar, Pakistan. 4 King Fahd Medical Research Center, King Abdulaziz University, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW, 2770, Australia; Novel Global Community Educational Foundation, Australia. 5 Bioinformatics and Medical Informatics Research Center, San Diego State University, San Diego, CA, 92182, USA. Electronic address: Patel3@rohan.sdsu.edu. Abstract BACKGROUND: Acetylcholinesterase (AChE), a serine hydrolase, is primarily responsible for the termination of signal transmission in the cholinergic system, owing to its outstanding hydrolyzing potential. Its substrate acetylcholine (ACh), is a neurotransmitter of the cholinergic system, with a predominant effect on motor neurons involved in memory formation. So, by decreasing the activity of this enzyme by employment of specific inhibitors, a number of motor neuron disorders such as myasthenia gravis, glaucoma, Lewy body dementia, and Alzheimer's disease, among others, can be treated. However, the current-available AChE inhibitors have several limitations in terms of efficacy, therapeutic range, and safety. SCOPE AND APPROACH: Primarily due to the non-compliance of current therapies, new, effective and safe inhibitors are being searched for, especially those which act through multiple receptor sites, but do not elicit undesirable effects. In this regard, the evaluation of phytochemicals such as flavonoids, can be a rational approach. The therapeutic potential of flavonoids has already been recognized agaisnt several ailments. This review deals with various plant-derived flavonoids, their preclinical potential as AChE inhibitors, in established assays, possible mechanisms of action, and structural activity relationship (SAR). RESULTS AND CONCLUSIONS: Subsequently, a number of plant-derived flavonoids with outstanding efficacy and potency as AChE inhibitors, the mechanistic, their safety profiles, and pharmacokinetic attributes have been discussed. Through derivatization of these reported flavonoids, some limitation in efficacy or pharmacokinetic parameters can be addressed. The selected flavonoids ought to be tested in clinical studies to discover new neuro-therapeutic candidates. Copyright © 2018 Elsevier Masson SAS. All rights reserved. KEYWORDS: Acetylcholinesterase inhibition; Flavonoids; Medicinal plants; SAR; Underlying mechanisms PMID: 29635895 DOI: 10.1016/j.biopha.2018.03.007