Hybridization of Curcumin Analogues with Cinnamic Acid Derivatives as Multi-Target Agents Against Alzheimer’s Disease Targets

Abstract

The synthesis of the new hybrids followed a hybridization with the aid of hydroxy-benzotriazole (HOBT) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI.HCL) in dry DMF or thionyl chloride between curcumin analogues and cinnamic acid derivatives. IR, 1H-NMR, 13C-NMR, LC/MS ESI+, and elemental analysis were used for the confirmation of the structures of the novel hybrids. The lipophilicity values of compounds were calculated theoretically and experimentally via the reversed chromatography method as RM values. The novel derivatives were studied through in vitro experiments for their activity as antioxidant agents and as inhibitors of lipoxygenase, cyclooxygenase-2, and acetyl-cholinesterase. All the compounds showed satisfying anti-lipid peroxidation activity of linoleic acid induced by 2,2′-azobis(2-amidinopropane) hydrochloride (AAPH). Hybrid 3e was the most significant pleiotropic derivative, followed by 3a. According to the predicted results, all hybrids could be easily transported, diffused, and absorbed through the blood–brain barrier (BBB). They presented good oral bioavailability and very high absorption with the exception of 3h. No inhibition for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was noticed. According to the Ames test, all the hybrids induced mutagenicity with the exception of 3d. Efforts were conducted a) to correlate the in vitro results with the most important physicochemical properties of the structural components of the molecules and b) to clarify the correlation of actions among them to propose a possible mechanism of action. Docking studies were performed on soybean lipoxygenase (LOX) and showed hydrophobic interactions with amino acids. Docking studies on acetylcholinesterase (AChE) exhibited: (a) hydrophobic interactions with TRP281, LEU282, TYR332, PHE333, and TYR336 and (b) π-stacking interactions with TYR336.

Action Mechanisms of Curcumin in Alzheimer’s Disease and Its Brain Targeted Delivery

“…v . Glutathione [ 3 , 93 ], lipid peroxidation [ 56 , 87 ], caspase activity [ 94 , 95 ], ROS activity [ 96 ], Ache activity [ 97 , 98 , 99 ] assays were used. vi .…”

“…Neuroinflammatory markers: immunohistochemistry [87][88][89][90], Western blotting [91], qRT-PCR analysis [91,92] and ELISA assay [86,92]. v. Glutathione [3,93], lipid peroxidation [56,87], caspase activity [94,95], ROS activity [96], Ache activity [97][98][99] assays were used. vi.…”

An Investigation into the Interaction between Double Hydroxide-Based Antioxidant Benzophenone Derivatives and Cyclooxygenase 2

“…Oxidative stress and inflammation are closely connected with each other, involving complicated feedforward and feedback loops. Increased levels of ROS have been found in many inflammation associated diseases [34,63]. Thus, the use of a single agent targeting COX2 enzyme along with oxidative stress process would probably be favorable.…”

Herbal Formula Huangqi Guizhi Wuwu Decoction Attenuates Paclitaxel-related Neurotoxicity via Inhibition of Inflammation and Oxidative Stress

“…For instance, paeoni orin exerts neuroprotective effect by attenuating oxidative stress through Nrf2 activation in diabetic peripheral neuropathy mice [23]. 6-Gingerol, cinnamic acid, and formononetin have been shown to play antioxidant and anti-in ammatory roles in several neurological diseases, such as ischemic brain damage, Alzheimer's disease, and oxaliplatin-induced peripheral neuropathy [24][25][26]. Both KEGG pathway enrichment and network analyses predicted the PI3K-Akt and Toll-like receptor pathways as the key signalling pathways that mediate the protective effect of HGWD against PIPN (Fig.…”