Design, Synthesis, and Activity Study of Cinnamic Acid Derivatives as Potent Antineuroinflammatory Agents

Abstract

Neuroinflammatory cytokines are promising therapeutic targets for the treatment of Alzheimer's disease. Herein, we described our efforts toward the investigation of cinnamic acid derivatives as antineuroinflammatory agents. Intensive structural modifications led to the identification of compound 4f as the most effective antineuroinflammatory agent in vitro. The oral administration of compound 4f could reverse lipopolysaccharide (LPS)-induced memory disturbance and normalize glucose uptake and metabolism in the brains of mice. Further biological studies in vivo revealed that compound 4f was directly bound to the mitogenactivated protein kinase (MAPK) signaling pathway, resulting in suppression of its downstream signaling pathway by blocking neuroinflammatory progression. Docking studies showed that compound 4f could be inserted into the active pocket of interleukin-1β (IL-1β). Furthermore, it was confirmed that compound 4f formed hydrogen bonds with SER84 to enhance the binding affinity. Taken together, these results are of great importance in the development of cinnamic acid derivatives for the treatment of Alzheimer's disease.

Discovery of Coixol Derivatives as Potent Anti-inflammatory Agents

“…The Boc protecting group of 3a – d was hydrolyzed to form the intermediates 4a – d , which were then condensed with differently substituted cinnamic acids in the presence of EDCI and HOBT to yield compounds 6a – n (Scheme ). Aromatic heterocyclic acrylic acids ( 8a –h) were synthesized through a Knoevenagel condensation reaction and subsequently condensed with intermediates 4a – d to yield compounds 9a – k (Scheme ). As illustrated in Scheme , compound 11a was synthesized by condensing furoic acid ( 10a ) with intermediate 4a .…”

“…24 overexpression of NO and IL-1β. 25 Compounds 9 and 10 functioned as iNOS inhibitors, providing relief from neuroinflammation. 26,27 Considering the anti-inflammatory capacity of coixol, we revealed two series of coixol derivatives combined with cinnamic acid and explored their anti-inflammatory activities in vitro and in vivo in this work.…”

Simple phenylpropanoids: recent advances in biological activities, biosynthetic pathways, and microbial production

“…50 By combining t -CA and a d -amino acid, a unique anti-neuroinflammatory compound was synthesised with some efficacy against AD, and was found to be able to bind strongly the proinflammatory cytokine interleukin-1β (IL-1β). 51 Recently, a number of non-clinical trials have supported antidepressant effects of phenylpropanoids. FA can achieve significant alleviation of depression in animal models by enhancing monoamine oxidase A (MOA) activity, promoting hippocampal nerve regeneration, anti-oxidative stress, and anti-inflammatory activity, and activating the protein kinase B/collapsin response mediator protein 2 (AKT/CRMP2) signalling pathway.…”

Anti-Neuroinflammatory Potential of Natural Products in the Treatment of Alzheimer’s Disease

“…Neuron damage acts as damage-associated molecular patterns (DAMPs) [ 5 ], and in turn promotes the continuous activation of microglia and astrocytes to produce persistent chronic neuroinflammation. It leads to progressive neuronal apoptosis, accelerates brain damage and finally forms AD pathological characteristics [ 57 ].…”