Thiazole-Bearing 4-Thiazolidinones as New Anticonvulsant Agents

Mariia Mishchenko,Sergiy Shtrygol,Danylo Kaminskyy,Roman Lesyk

doi:10.3390/scipharm88010016

Abstract

Here, we describe the synthesis and anticonvulsant activity of thiazole-bearing hybrids based on 2-imino-4-thiazolidinone and 2,4-dioxothiazolidine-5-carboxylic acid cores. The structure of target compounds was based on the following: (i) A combination of two thiazole cores; (ii) similarity to ralitolin’s structure; (iii) the compliance with structural requirements for the new anticonvulsants. Target compounds were synthesized via known approaches based on Knoenavegel reaction, alkylation reaction, and one-pot three-component reaction. Anticonvulsant properties of compounds were evaluated in two different models—pentylenetetrazole-induced seizures and maximal electroshock seizure tests. Among the tested compounds 5Z-(3-nitrobenzylidene)-2-(thiazol-2-ylimino)-thiazolidin-4-one Ib, 2-[2,4-dioxo-5-(thiazol-2- ylcarbamoylmethyl)-thiazolidin-3-yl]-N-(2-trifluoromethylphenyl)acetamide IId and (2,4-dioxo-5- (thiazol-2-ylcarbamoylmethylene)-thiazolidin-3-yl)acetic acid ethyl ester IIj showed excellent anticonvulsant activity in both models. The directions of compounds modification based on SAR aspects were discussed. The results of the study provide a basis for further study of the anticonvulsant properties of selected thiazole-thiazolidinones.

Highlights

Epilepsy is one of the most common chronic neurological diseases, affecting up to 1% of the human population [1]
The results of the study provide a basis for further study of the anticonvulsant properties of selected thiazole-thiazolidinones
According to the WHO, more than 50 million people worldwide suffer from epilepsy [2]

Summary

Introduction

Epilepsy is one of the most common chronic neurological diseases, affecting up to 1% of the human population [1]. A significant part of patients cannot obtain a stable anticonvulsant effect under monotherapy [6], and about 30% of patients have refractory epilepsy and need treatment with drug combinations [7,8]. Increasing the frequency of attacks and side effects, the transformation of attacks and deterioration of the electroencephalogram are observed in some patients under anti-epileptic drug treatment. This is largely due to inadequate effectiveness of anticonvulsants, the need for their high doses, and as a result, their dose-dependent side effects, namely violations of behavioral reactions, emotional state, cognitive abilities, the development of encephalopathy, and mental disorders [9]. The search for new efficient and safety anticonvulsants is of special interest

Methods

Discussion

Conclusion