Chandran, Remya and Kumar, Mantosh and Kesavan, Lakshmi and Reena, Sarah Jacob and Omkumar, R.V. (2021) Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase – Design, synthesis and biological evaluation. Computational and Structural Biotechnology Journal, 19. pp. 4517-4537. ISSN 2001-0370

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Abstract

The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimer’s disease (AD). Tacrine, a potent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD. Tacrine is also a low affinity antagonist of N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to its hepatotoxicity. With an aim to develop novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, we performed in silico structure-based modifications on tacrine, chemical synthesis of the derivatives and in vitro validation of their activities. Nineteen such derivatives showed inhibition with IC50 values in the range of 18.53 ± 2.09 – 184.09 ± 19.23 nM against AChE and 0.27 ± 0.05 – 38.84 ± 9.64 μM against NMDAR. Some of the selected compounds also protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, 201 and 208 exhibited in vivo efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Additionally, several of these synthesized compounds also exhibited promising inhibitory activitiy against butyrylcholinesterase. MTDL-201 was also devoid of hepatotoxicity in vivo. Given the therapeutic potential of MTDLs in disease-modifying therapy, our studies revealed several promising MTDLs among which 201 appears to be a potential candidate for immediate preclinical evaluations.

Item Type:	Article
Uncontrolled Keywords:	Alzheimer’s disease MTDLs Structure-based drug design Polypharmacology Tacrine Acetylcholinesterase NMDA receptor Neuroprotection
Subjects:	Molecular Neurobiology
Depositing User:	Central Library RGCB
Date Deposited:	29 Sep 2021 11:39
Last Modified:	29 Sep 2021 11:39
URI:	http://rgcb.sciencecentral.in/id/eprint/1042

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