Abstract

Abstract

An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields via protecting group-free stepwise unsymmetric diacylation of piperazine using N-acylbenzotiazole. Compounds 3f, 3d, and 3i exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid 3f was found to exhibit higher in vitro potency than donepezil with IC50 = 18 ± 0.2 nM, 29.9 ± 0.15 nM for 3f and donepezil, respectively. 3f was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds 3f, 3d, and 3i are drug-like and can penetrate blood–brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs.

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Title
Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening
Author
Agha, Khalid A 1 ; Abo-Dya, Nader E 2 ; Abdul Rashid Issahaku 3 ; Clement Agoni 3 ; Soliman, Mahmoud E S 3 ; Abdel-Aal, Eatedal H 4 ; Abdel-Samii, Zakaria K 4 ; Ibrahim, Tarek S 5 

1  Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, Fayoum University , Fayoum , Egypt, Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University , Zagazig , Egypt 
2  Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University , Zagazig , Egypt, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk , Tabuk , Saudi Arabia 
3  Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal , Durban , South Africa 
4  Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University , Zagazig , Egypt 
5  Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University , Zagazig , Egypt, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University , Jeddah , Saudi Arabia 
Pages
1241-1256
Publication year
2022
Publication date
Dec 2022
Publisher
Taylor & Francis Ltd.
ISSN
14756366
e-ISSN
14756374
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1080/14756366.2022.2068147
ProQuest document ID
2727915957
Copyright
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.