Biological evaluation and molecular Docking studies of the prepared chalcone derivatives as potential anti-Alzheimer agents

Alzheimer's disease (AD) is a neurological disorder characterized by memory loss, language difficulties, and the loss of planning and coordination skills. Research done by neurologists suggest that the decline in acetylcholine and the accumulation of pathological forms of amyloid beta plaques produced by both the β- and γ-secretase enzymes in the brain as some of the primary causes of AD. Due to the multifactorial pathway associated with the progression of the disease, the inhibition of cholinesterase, β-secretase and other anti-inflammatory related enzymes have been reported as one of the major approaches in curbing the symptoms associated with it. Organic compounds containing the chalcone, sulfonyl, and allyl frameworks have been reported to possess cholinesterase, β-secretase, cyclooxygenase (COX) and lipoxygenase (LOX) inhibitory activities. As a result, we synthesized the allyl chalcones and their sulfonyl derivatives from commercially available 2,4-dihydroxyacetophenone, and evaluated them as potential anti-Alzheimer agents through in-vitro enzymatic assays as cholinesterase, β-secretase, LOX-5 and COX-2 inhibitors. Although, poor inhibitory effects were observed for the chalcone sulfonates against cholinesterase and β-secretase, derivatives 3c, 3e and 3 g exhibited significant inhibitory effects against these enzymes. With the exception of 3a, 3b and 3e with good COX-2 inhibitory activity, other derivatives showed poor anti-inflammatory activity. Enzyme kinetics complemented by molecular docking studies performed on 3e suggests a mixed mode of inhibition of the compound towards these enzymes. In our view, 3e with significant cholinesterase, cyclooxygenase and lipoxygenase inhibitory activities could potentially serve as multi-target drug-lead candidate against AD.