8‐Substituted 3‐Arylcoumarins as Potent and Selective MAO‐B Inhibitors: Synthesis, Pharmacological Evaluation, and Docking Studies

Abstract

Neurodegenerative disorders are becoming more prevalent given the increase in the aging population. This has inspired active research in the development of new drugs that could mark an important advance in the treatment of complex diseases such as Alzheimer's and Parkinson's. With the aim of finding new MAO-B-selective inhibitors, we report the synthesis, in vitro evaluation, and docking simulation of a new series of 3-arylcoumarins variously substituted at the 8-position. Most of the studied compounds show high affinity and selectivity for the hMAO-B isoform, with IC₅₀ values in the low micro- to nanomolar range. Some of them have greater hMAO-B inhibitory activity and selectivity than the reference compound, selegiline. Compounds 7 and 8 are the most active of this series, with compound 8 being fivefold more potent against MAO-B and severalfold more selective than selegiline. Docking experiments were carried out with hMAO-B crystal structures, providing new information about the enzyme-inhibitor interaction and the potential therapeutic application of the new 8-substituted 3-arylcoumarins.

Quantum chemical analysis of potential anti-Parkinson agents

“…11,12 A few reports on docking study of 3-substituted coumarins may be found in the literature. 13,14 To provide additional insights into the binding mode, molecular docking studies of 3-phenylcoumarins (1-9) (scheme 1) 5,15 were performed in the active site of MAO-B. Given the imperfection of docking simulations in providing the information on intermolecular binding energy components, 16 subsequent to the docking studies, we estimated the participation of each amino acid in total binding energy via an Scheme 1.…”

3‐Amidocoumarins as Potential Multifunctional Agents against Neurodegenerative Diseases

“…In this work, variously substituted 3-amidocoumarins are described that exert neuroprotection in vitro against hydrogen peroxide in rat cortical neurons, as well as antioxidant activity in a1 ,1-diphenyl-2-picrylhydrazyl (DPPH·) radicals cavenging assay.S elective and reversible inhibitors of the MAO-B isoform were identified. [14] Coumarins have been found to act as antioxidants and anti-inflammatory agents, [15] neuroprotective agents, [16,17] antidepressants, [18] anticonvulsants, [19] antibacterials, [20] antivirals, [21] anticancera gents, [22,23] anticoagulants, [24] anti-hypertensives, [25] ande nzyme inhibitors, [26][27][28][29][30][31][32][33] amongo ther activities. However,t he compounds describedh erein adhere to Lipinski'sr ule of five, suggesting that this novel scaffold has desirable properties for the development of potential drug candidates.…”

“…Interestingly,i nt he case of the 3-benzamidocoumarins, substi-tution at position 4w ith ah ydroxy group abolishes MAO-B activity,but the compoundsr emain active in the neuroprotection model.F urther evaluation of 3-heteroarylamide derivatives indicatest hat it is the nature of the heterocycle that determines the neuroprotective effects.E valuationi naparallela rtificial membrane permeability assay (PAMPA) highlighted the need to furtheri mprovet he blood-brain barrier permeability of this compound class. [27][28][29][30][31][32][33] In recent years, simple coumarins substituted at positions 3o r4have been described to exhibit activity as inhibitors of cholinesterases (ChE), both acetylcholinesterase (AChE)a nd butyrylcholinesterase (BuChE). neuronal degeneration of the dopaminergic nigrostriatalp athway.…”

“…[10] Nonetheless, all approved PD pharmacotherapies have limited efficacy, do not prevent the progression of the disease, and are associated with adverse motor and non-motors ide effects. [34] Ta king into account the background of our research group ( Figure 1) [28][29][30][31][32][33] and the knowledge that MAO activity generates ROS that cause neuronal cell death,t he present work provides an overview on the potentialo fv ariously substituted 3-amidocoumarins as multifunctional agents. Throughoutt he history of medicine, nature has played ak ey role as source of inspiration in the development of drugs with important biological activities.…”

Synthesis and electrochemical study of new 3-(hydroxyphenyl)benzo[f]coumarins

“…Coumarins are also described as antiviral, vasorelaxant, antioxidant, antimicrobial, anticancer, anti-inflammatory and enzymatic inhibitors [22][23][24][25][26][27][28][29][30][31][32][33], but limited data is available concerning their antioxidant activity [22,30,[34][35][36].…”