Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N-benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer’s disease

Abstract

A novel family of cinnamic acid derivatives has been developed to be multifunctional cholinesterase inhibitors against AD by fusing N-benzyl pyridinium moiety and different substituted cinnamic acids. In vitro studies showed that most compounds were endowed with a noteworthy ability to inhibit cholinesterase, self-induced Aβ (1–42) aggregation, and to chelate metal ions. Especially, compound 5l showed potent cholinesterase inhibitory activity (IC50, 12.1 nM for eeAChE, 8.6 nM for hAChE, 2.6 μM for eqBuChE and 4.4 μM for hBuChE) and the highest selectivity toward AChE over BuChE. It also showed good inhibition of Aβ (1–42) aggregation (64.7% at 20 μM) and good neuroprotection on PC12 cells against amyloid-induced cell toxicity. Finally, compound 5l could penetrate the BBB, as forecasted by the PAMPA-BBB assay and proved in OF1 mice by ex vivo experiments. Overall, compound 5l seems to be a promising lead compound for the treatment of Alzheimer’s diseases.

Cinnamic acid activates PPARα to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer's disease mouse model

“…Thirdly, cinnamic acid is readily available and much cheaper compared to available AD therapeutics. Importantly, cinnamic acid derivatives have been demonstrated to function as cholinesterase inhibitors and might have therapeutic beneficial in AD ( Chen et al, 2018 ; Lan et al, 2017 ). In-vitro study by Zhang et al has shown that one of the derivatives, compound 5I, inhibits choloinesterase activity, prevents aggregation of Aβ42 and is neuroprotective against amyloid-stimulated cell toxicity ( Lan et al, 2017 ).…”

Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer’s disease

“…Several studies highlighted their role as an antioxidant, antiinflammatory, antidiabetic, and anticancer agents . They also possess various pharmacological properties that can work against diverse neurological disorders . A cinnamic acid 2,3‐dimethyl derivative extracted from the leaves of pycnanthus angolensis has been reported for its potential cholinesterase inhibitory activity .…”

“…A cinnamic acid 2,3‐dimethyl derivative extracted from the leaves of pycnanthus angolensis has been reported for its potential cholinesterase inhibitory activity . Recently, a docking study suggested an interaction of N‐benzyl pyridinium moiety with the catalytic anionic site of AChE and the interaction of heterocyclic moiety with the peripheral anionic site of AChE that leads to stacking interactions . The hybrid of cinnamic acid with benzyl pyridinium is suggested to be a dual‐acting AChE .…”

“…Recently, a docking study suggested an interaction of N‐benzyl pyridinium moiety with the catalytic anionic site of AChE and the interaction of heterocyclic moiety with the peripheral anionic site of AChE that leads to stacking interactions . The hybrid of cinnamic acid with benzyl pyridinium is suggested to be a dual‐acting AChE . Novel cinnamic acid derivative, E)‐4‐(3‐(3,4‐dimethoxyphenyl)acrylamido)‐1‐(3‐methylbenzyl) pyridin‐1‐ium bromide, has been reported to possess high AChE inhibitory potential in the range of 7.5‐30 nmol/L concentrations with IC 50 values of 8.6 nmol/L.…”

“…Moreover, this derivative has also been reported for anti‐Alzheimer’s properties such as inhibition of Aβ aggregation, neuroprotection against amyloid‐induced toxicity, and ability to penetrate the blood‐brain barrier. This novel compound has been suggested as a lead compound for the treatment of AD . Cinnamic acid derivatives, 3‐methyl‐3‐butenyl‐trans‐caffeate (57.14%) and 3,4 dimethoxycinnamic acid (56.4%) extracted from Egyptian propolis (bee glue), have also been reported for their AChE inhibitory activity via blockage of AChE active site .…”