Multi-Target Directed Ligands (MTDLs): Promising Coumarin Hybrids for Alzheimer's Disease

Alzheimer's disease (AZD) is an age-associated neurodegenerative disorder and is one of the common health issues around the globe. It is characterized by memory loss and a decline in other cognitive domains, including executive function. The progression of AZD is associated with complex events, and the exact pathogenesis is still unrevealed. Various mechanisms which are thought to be associated with the initiation of AZD include a decreased concentration of acetylcholine (ACh), deposition of amyloid-D (AD) peptide, dyshomeostasis of redox metal ions, and prolonged oxidative stress. Due to the simultaneous progression of diverse pathogenetic pathways, no ideal therapeutic agent has been developed to date. The drugs which are available against AZD provide only symptomatic benefits and do not have disease-modifying activity. Therefore, in search of ideal therapeutic candidates, the concept of molecular hybrids has been under keen investigation for the past few years. Hybrid molecules are able to inhibit or activate or modify the physiology of more than one target simultaneously. Coumarin scaffold have shown the excellent potential of ACh esterase inhibition, MAO-B inhibition, and anti-AD aggregation. In the present review, we have focused on different reported coumarin hybrids as multi-target-directed agents against AZD. These include hybrids of coumarin with carbazole, benzofuran, dithiocarbamate, quinoline, pargyline, tacrine, N-benzyl pyridinium, donepezil, purine, piperidine, morpholine, aminophenol, benzylamino, halophenylalkylamidic, thiazole, thiourea, hydroxypyridinone, triazole, piperazine, chalcone, etc. Along with the therapeutic potentials of these hybrids, important clinical investigations and the structure-activity relationship have also been discussed in this compilation.

Automated summary

Alzheimer's disease is an age-associated neurodegenerative disorder characterized by memory loss and cognitive decline. The exact pathogenesis of the disease is still unknown, with mechanisms such as decreased acetylcholine concentration and amyloid deposition believed to be involved. Current drugs against Alzheimer's provide only symptomatic relief, prompting the investigation of molecular hybrids as potential multi-target therapies. Coumarin hybrids show promise in targeting multiple pathways associated with Alzheimer's, but further research is needed to fully understand their therapeutic potential.