Design, synthesis and pharmacological evaluation of carboxamide and carbothioamide derivatives of 1,3,4-thiadiazole as the inhibitors of acetylcholinesterase and oxipiperazine)ative stress for the management of cognitive debility

Abstract

Acetylcholinesterase has been a promising target for the development of putative therapeutics against cognitive decline. The deleterious effect of oxidative stress on the learning and memory paradigms of an individual has also been well documented. In view of this and our previous findings on the ameliorative effects of amide derivatives of 1,3,4-thiaidiazoles on cognitive deterioration, the present study demonstrated the design, synthesis and pharmacological evaluation of carboxamides and carbothioamide derivatives of 1,3,4-thiadiazole. Novel carboxamide and carbothioamide derivatives were synthesised and characterised by various spectral and elemental techniques. Their effects on memory were studied by employing scopolamine induced amnesia in two behavioural animal models: Morris water maze and passive avoidance (dose of 0.5 mg/kg) with reference to the standard, Rivastigmine. In vitro AChE inhibition was studied at five different concentrations using the homogenised fraction of the decapitated mice brain as the source of the enzyme. Biochemical estimation of AChE, oxidative and nitrosative stress parameters have also been facilitated. Computational docking studies have been performed on human recombinant AChE (PDB ID: 4EY7) to assess the binding conformation of the molecules. The results indicated that the carbothioamide analogues 13a, 9b and 10b were found to be the most promising in the alleviation of cognitive decline induced by scopolamine. Among the carboxamide analogues, 8b has shown promising effect in the alleviation of cognition decline. Our results suggested the possible role of these derivatives in the mediation of cholinergic pathway and attenuation of oxidative stress resulting in the effective management of cognitive dysfunction.