Design, Synthesis, and Structure–Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer’s Disease

Abstract

Dementia is a neurological condition commonly correlated with Alzheimer’s disease (AD), and it is seen with many other central nervous system (CNS) disorders. The restricted number of medications is not appropriate to offer enough relief to enhance the quality of life of patients suffering from this symptom; thus, all therapeutic choices should be carefully assessed. In this study, new thiazolylhydrazone derivatives (2a–2l) were designed and synthesized based on the cholinergic hypothesis. Their chemical structures were confirmed by 1H NMR, 13C NMR, and HRMS spectrometric techniques. The ADME (absorption, distribution, metabolism, elimination) parameters of the synthesized compounds were predicted by using QikProp 4.8 software. It was concluded that all compounds presented satisfactory drug-like characteristics. Furthermore, their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro were also tested by modified the Ellman spectrophotometric method. According to the results, all compounds showed a weak inhibitory effect on BChE. On the other hand, most of the compounds (2a, 2b, 2d, 2e, 2g, 2i, and 2j) had a certain AChE inhibitory activity, and the IC50 values of them were calculated as 0.063 ± 0.003, 0.056 ± 0.002, 0.147 ± 0.006, 0.040 ± 0.001, 0.031 ± 0.001, 0.028 ± 0.001, and 0.138 ± 0.005 µM, respectively. Among these derivatives, compound 2i was found to be the most active agent in the series with an IC50 value of 0.028 ± 0.001 µM, which indicated an inhibition profile at a similar rate as the reference drug, donepezil. The potential binding modes of compounds 2a, 2b, 2e, 2g, and 2i with AChE were investigated and compared with each other by the molecular docking studies. The results showed that these compounds were strongly bound up with the AChE enzyme active site with the optimal conformations.

Design, Synthesis, and Evaluation of Novel 2H-Benzo[b][1,4]thiazin-3(4H)-one Derivatives as New Acetylcholinesterase Inhibitors

“…To observe the BBB permeability of the active compounds 3i and 3j , the parallel artificial membrane permeability assay (PAMPA) was performed as previously described [ 21 ]. Briefly, the solutions of each compound were prepared in dimethyl sulfoxide (DMSO) at 10 mM and then diluted with PBS (Phosphate-Buffered Saline; pH = 7.4) to obtain the donor drug solution with the nominal final concentration of 100 μM (297 μL of buffer + 3 μL of DMSO drug solution).…”

“…Compounds with dual binding affinity to both active binding sites of the AChE enzyme, such as donepezil, have an excellent AChE inhibition profile [ 19 , 20 ]. In continuation of our previous research [ 21 ], in this work, we designed and synthesized a series of donepezil-based molecules with an evaluation of their AChE inhibitor activity in comparison to donepezil, as shown in Figure 1 .…”

Thiazole: A Versatile Standalone Moiety Contributing to the Development of Various Drugs and Biologically Active Agents

“…Among the synthesized compound, 123 was found to be the most active agent in the series with an IC 50 value of 0.028 ± 0.001 µM, which indicated an inhibition profile similar to the reference drug, donepezil. The highly active compound 123 might exhibit anticholinesterase activity due to the presence of hydroxyl and methoxy moieties at the third and fourth positions of the phenyl ring [158].…”

Discovery of New 1,3,4-Oxadiazoles with Dual Activity Targeting the Cholinergic Pathway as Effective Anti-Alzheimer Agents

“…15 Studies have shown that rivastigmine's dual inhibitory activity elicits a better patient response in terms of stabilization of diseases, improvement in cognitive function, and reduction in the burden of concomitant psychoactive treatment. 16 Although many researchers have focused on finding new small molecules structurally derived from FDA-approved drugs such as tacrine and donepezil, 17 some have discovered other five-membered heteroaryls such as thiazoles 18 and 1,3,4oxadiazoles 19 as multitargeted hybrids for AD.…”