Synthesis and evaluation of 7-substituted coumarin derivatives as multimodal monoamine oxidase-B and cholinesterase inhibitors for the treatment of Alzheimer's disease

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs<strong> </strong>

“…Figure 4 shows the strategy followed in some recent publications to combine anti AD drugs donepezil or tacrine that inhibit ChEs with coumarin structures that inhibit MAO. The combination of donepezil and coumarin shown in Figure 5 met with some success with the best compound showing micromolar AChE and BChE inhibition (IC 50 = 9.10 µM and 5.90 µM, respectively), and selective hMAO-B inhibition (IC 50 = 0.30 µM), but the potency on the four enzymes varied widely across the series [14]. Using tacrine as in the example in Figure 4b was less successful because the large size decreased the inhibition of MAO (IC 50 = 10-100 µM), although the inhibtion of ChEs remained in the sub-micromolar range [129].…”

Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

“…A number of review papers describe the importance of coumarin compounds in the field of neurodegenerative disorders where they have shown inhibitory properties towards monoamine oxidases, cholinesterases, β-and γ-secretase and other targets involved in the progression of neurodegenerative disorders [23][24][25]. Similarly, coumarin derivatives described in this article also demonstrated neuronal enzyme inhibitory properties [26]. Therefore, the effective utilization of the coumarin scaffold may essentially be hampered by its versatility unless sufficient selectivity can be ensured.…”

“…Synthesis methods of the compounds described in this article are described in detail in previous publications by the drug design group at UWC [26].…”

“…Early identification and structure activity relationship evaluation of alternative pharmacological effects, over-and-above standard cytotoxicity assays, may increase the viability of coumarin-based antimycobacterial and/or neuroprotective agents. As part of a collaborative project, a number of 7-substituted coumarin derivatives initially designed and synthesized as multifunctional neuronal enzyme inhibitors [26], were found to exhibit promising antimycobacterial activity (see Table 1) The compounds, originally designed to incorporate coumarin structures known to show monoamine oxidase B (MAO-B) inhibition [27] and selected structural elements of donepezil, a selective acetylcholinesterase (AChE) inhibitor [28], were able to selectively inhibit human MAO-B as well as electric eel AChE and equine butyrylcholinesterase (BuChE) [26]. Further evaluation of the structure activity relationships for selectivity and specific characteristics of these compounds were therefore required in order to assess the viability of the compounds as neuronal enzyme inhibitors and/or antimycobacterial clinical agents.…”

Synthesis, Crystal Structures, Molecular Docking and MAO-B Inhibitory Activity of Transition Metal Complexes Derived from 2-(4-(Pyridin-2-yl)piperazin-1-yl)acetic Acid

“…6 Therefore, MAO-B inhibitors can be used to treat the neurodegenerative disorders such as Aizheimer's disease (AD) and Parkinson's disease (PD). [7][8][9] Kinds of heterocyclic scaffolds such as chalcone, 10 coumarin, 11 pyrazoline 12 and oxadiazole 13 derivatives have been demonstrated as MAO-B inhibitors. Recently, pyridoxine-resveratrol hybrids Mannich base derivatives have been reported as MAO-B inhibitors by Yang et al 14 As mentioned above, most reported MAO-B inhibitors are organic heterocyclic molecules while MAO-B inhibitors based on metal complexes are seldom discussed.…”