ABSTRACT
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves different pathogenic mechanisms. In this regard, the goal of this study was the design and synthesis of new compounds with multifunctional pharmacological activity by molecular hybridization of structural fragments of curcumin and resveratrol connected by an N-acyl-hydrazone function linked to a 1,4-disubstituted triazole system. Among these hybrid compounds, derivative 3e showed the ability to inhibit acetylcholinesterase activity, the intracellular formation of reactive oxygen species as well as the neurotoxicity elicited by Aß42 oligomers in neuronal SH-SY5Y cells. In parallel, compound 3e showed a good profile of safety and ADME parameters. Taken together, these results suggest that 3e could be considered a lead compound for the further development of AD therapeutics.
Subject(s)
Alzheimer Disease/drug therapy , Triazoles/chemistry , Triazoles/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Cells, Cultured , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacokinetics , Cholinesterase Inhibitors/pharmacology , Curcumin/pharmacokinetics , Curcumin/pharmacology , Humans , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/pharmacology , Pharmacokinetics , Reactive Oxygen Species/metabolism , Resveratrol/pharmacokinetics , Resveratrol/pharmacology , Triazoles/pharmacokineticsABSTRACT
Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 µM, and a similar inhibition profile of the human isoform (IC50 = 5.7 µM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 µM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development.
