Biological Evaluation and Synthesis of Benzothiazole- Piperazine Derivatives as Probable Cholinesterase Inhibitors to Treat Alzheimer’s Disease

Abstract

Background: Alzheimer’s disease is the most prevalent cause of progressive dementia among older adults. One of the main causes of the disease is deficiency of the cholinergic system. Nevertheless, some acetyl cholinesterase inhibitors have played a significant role in controlling disease progression.

Aim and objectives: In continuation of the development of new acetylcholinesterase inhibitors, benzothiazole-piperazine derivatives as probable inhibitors were synthesized and evaluated.

Materials and Methods: Acylation of benzothiazole-2- amine with chloroacetyl chloride yielded 2-chloro-N-(benzothiazole-2-yl) acetamide which undergoes a substitution reaction with piperazine to produce intermediate 3.  Reaction of intermediate 3 with the appropriate acyl chlorides or alkyl chloride produced the final compounds. Enzyme inhibitory potency was assessed by Ellman's test. The inhibitory activity of compounds on acetyl cholinesterase and butyryl cholinesterase enzymes was expressed as IC₅₀. Docking of the final derivatives in the active site of acetylcholinesterase (PDB ID: 1EVE) was performed.

Results: Unfortunately, the compounds failed to show inhibitory effects on cholinesterase enzymes with IC₅₀>100 µM values when compared with donepezil with IC₅₀ values 0.014 ± 0.0012 and 14.4 ± 15 µM on acetyl cholinesterase and butyryl cholinesterase enzymes respectively. Compound 4c with ΔG = -10.53 Kcal/mol was the best compound in docking studies.