Design and Synthesis of Coumarin-Curcuminoid Hybrids as Potential Multitargeting Neuroprotectants
Neurodegenerative diseases are among one of the most significant health challenges of the modern era. A key challenge in designing chemotherapeutics for neurodegenerative diseases is that multiple cellular mechanisms such as oxidative stress, glutamate-induced excitotoxicity, and neuroinflammation all contribute to neuronal cell death. Molecular hybridization, an emerging multitargeting drug design strategy, was employed as a synthetic method for identifying potential neuroprotectants. Coumarin and curcuminoids were selected for hybridization due to their possession of neuroprotective activity, including anti-inflammatory, antioxidizing and improved neuronal cell resistance. This study aimed to hybridize the two pharmacophores in order to design novel compounds with improved pharmacophoric features than the parenting compounds alone. Overall, two synthetic methods have been explored and synthetic routes for synthesizing starting materials for both methods have been established. The first route employed a modified Claisen condensation reaction—utilizing soft enolization— while the second employed an SN2 reaction. Of the two routes explored, the first was found to be unattractive due to its difficulty in synthesizing the targeted hybrid while the second was identified as a potential method given its success in generating two targeted hybrids.
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