Synthesis and biological evaluation of benzothiazin-4-ones: a possible new class of acetylcholinesterase inhibitors

Abstract

A series of nineteen benzothiazin-4-ones from N-(3-aminopropyl) piperidine, 4-(2-aminoethyl)morpholine or 1-(2-aminoethyl)piperidine, aliphatic or aromatic aldehyde and thiosalicylic acid, were synthesized in good yields by multicomponent one-pot reactions. The solvent was toluene and this efficient procedure afforded the desired heterocycles in 5 h. Identification and characterization were achieved by NMR and GC–MS techniques. In vitro AChE activities of all compounds were evaluated in cerebral cortex and hippocampus of rats and in general, the results in cortex were more promising than hippocampus. The benzothiazinone 5Bd showed the best AChE inhibition activity IC50 8.48 μM (cortex) and IC50 39.80 μM (hippocampus). The cytotoxicity of seven compounds in MCR-5 human fibroblast cell by SRB test in 24 h were evaluated and 5Bd suggest preliminary safety, showing no cytotoxicity at 100 µM. Finally, these important findings could be a starting point for the development of new AChE inhibitors agents and will provide the basis for new studies.

Synthesis of thiazolidin-4-ones and thiazinan-4-ones from 1-(2-aminoethyl)pyrrolidine as acetylcholinesterase inhibitors

“…Other studies have reported that the presence of pyrrolidine heterocycle in the synthesised products showed a potential inhibitory effect of AChE 38 , 39 . In addition, previous research from our research group has demonstrated the synthesis of benzothiazinan-4-one and the potential of some compounds in inhibited the AChE activity from hippocampus and cerebral cortex from rats, demonstrating the importance of this heterocycle in the cholinergic action 27 . Comparing these reports with the study proposed in this paper, I point out that the union of thiazolidin-4-one and thiazinan-4-one with pyrrolidine heterocycle aimed at enhancing AChE inhibition activity, as indeed observed with the results found.…”

“…also reported that Rattus norvegicus AChEs structures must be very similar to human structure and have properties identical to the active site. Also, although some studies use the isolated form of AChE, the use of crude homogenised from rat’s brain structures, as used in the present work, is widely used and proves to be an important source of AChE for in vitro studies 27 .…”

“…We have been studying these classes of heterocycles in a few years 23–26 and in continuation of our research programme, this work aims to synthesise novel thiazolidin-4-ones and thiazinan-4-ones from a specific amine, the 1–(2-aminoethyl)pyrrolidine, affording compounds structurally similar to AChE that could act as AChE inhibitors (Figure 1). The same strategy was used in previous work with good results 27 . Another goal is the AChE inhibitory activity and cytotoxicity of synthesised compounds, contributing to the search for new compounds that can be used for the AD treatment.…”

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

“…In relation to GPx-like activity, most of the compounds were able to catalytically reduce peroxide production, and particularly 42a and 42b exhibited higher activities than ebselen used as reference drug. In the H 2 O 2 -sequestering activity, compounds 42a and 42b showed a similar effect to 41 , suggesting that these organoselenium hybrids could represent interesting innovation in the search for new multifunctional agents for AD treatment [ 84 ].…”

A green and efficient process for the synthesis of Benzothiazinones using Phosphate fertilizers MAP, DAP and TSP as heterogeneous catalysts

“…Currently, BTZ compounds were identified as a possible new class of acetylcholinesterase inhibitors for curing the symptoms of Alzheimer's disease (8).…”