Curcumin–Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders

Abstract

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin–coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11–18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.

Coumarin derivatives inhibit the aggregation of β-lactoglobulin

“… 18 Some coumarin hybrid molecules are also be designed as a multi-targeting agent to stop the fibrillation process in neurodegenerative disorders. 19 All these facts encourage us to investigate some polyphenolic coumarinoids as anti-fibrillating agents. Here, we have synthesized and characterized some polyphenoliccoumarinoids and applied them to check their anti-fibrillation power on the model protein β-lg.…”

Natural Antioxidant Compounds as Potential Pharmaceutical Tools against Neurodegenerative Diseases

“…Polymer-based nanostructures are a widely used and studied class of nanomaterials commonly exploited as nanocarrier systems. Similar to what has been previously discussed concerning lipid-based nanostructures, curcumin is once again one of the most studied natural antioxidants as cargo for nanocarriers. − The FDA-approved copolymer PLGA has been a widely used base for polymeric nanostructures loaded with curcumin due to its high biocompatibility and biodegradability . Some examples of curcumin-loaded PLGA nanostructures include nanoparticles able to prevent ROS accumulation in the SK-N-SH cell line, neuron targeting PLGA nanoparticles with antioxidant and antiamyloid properties, and curcumin-loaded PLGA nanostructures cofunctionalized with a BBB targeting peptide and the Aβ generation inhibitor S1 (PQVGHL peptide), able to attenuate the behavioral and neuropathological feature of AD in animal models .…”

“…The obtained hybrid-loaded PLGA nanoparticles demonstrated the ability to prevent ROS accumulation in the SH-SY5Y cell line. 129 Lactoferrin-based nanostructures have also been proposed as a potential delivery system for curcumin. In particular, lactoferrin-loaded nanostructures obtained through sol-oil chemistry with an average diameter of 43–60 nm were employed as a countermeasure for ROS accumulation in a rotenone-based in vitro PD model.…”

Design, synthesis, structural analysis and quantum chemical insight into the molecular structure of coumarin derivatives

“…Coumarin derivatives exhibit high bioavailability, solubility in most organic solvents and low toxicity that make them potential pharmaceutical candidates. 3 Several studies on coumarins have shown that they act as enzymatic inhibitory agents in neurodegenerative diseases, 4–7 and hence they are used as anti-Alzheimer 8–9 and anti-depressant drugs. 10 Coumarin and its derivatives have been identified with anti-HIV, 11 anti-influenza, 12 anti-viral 13,14 and anti-asthmatic properties.…”