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Central Nervous System Agents in Medicinal Chemistry

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ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

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Research Article

Design, Synthesis, and Pharmacological Evaluation of Novel Tacrine Derivatives as Multi-target ANTI-Alzheimer’s Agents In Rat Models

Author(s): Remya R.S.*, Ramalakshmi N., Muralidharan P. and Nalini C.N.

Volume 23, Issue 3, 2023

Published on: 21 September, 2023

Page: [175 - 193] Pages: 19

DOI: 10.2174/1871524923666230908094645

Price: $65

Abstract

Background: Alzheimer’s disease is a progressive neurodegenerative disorder for which no curative drugs are available and treatment available is just palliative.

Objectives: Current research focused on design of Tacrine-Flavone hybrids as multitargeted cholinesterase and monoamine oxidase B inhibitors.

Methods: A total of 10 Tacrine- Flavone hybrids were designed, synthesized and characterized. The in vitro neurotoxicity and hepatotoxicity of the synthesized compounds determined using SHSY5Y cell line and HEPG2 cell line. One most active compound (AF1) with least toxicity in in vitro studies was chosen for in vivo studies. Acute and subacute toxicity of the novel compound AF1 conducted on Wistar rats according to OECD guideline 423 and 407. The LD50 value of the novel compound calculated according to Finney’s method using Probit analysis. Anti-Alzheimer’s activity studies conducted on male Wistar rats. Behavioral studies conducted and AChE and MAO-B activity determined in rat brain.

Results and Discussion: All the compounds exhibited good inhibitory effect on MAO B and AChE. The neurotoxicity studies of the active compound AF1 did not show toxicity up to 100μg. The hepatotoxicity study of the most active compound AF1, showed the compound to be safe up to 200μg. The LD 50 value of the novel compound after a single oral administration was found to be 64 mg/kg bodyweight in rats. Subacute toxicity studies did not show any remarkable toxicity in the vital organs up to 40 mg/kg. Activity studies showed comparable results with standard at 20 mg/kg.

Conclusion: The results showed that the novel Tacrine-Flavone hybrids are multitarget-directed ligands, which are safe and active compared to tacrine and can be a promising lead molecule for further study.

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