MAO Inhibitors Research Articles

Theoretical investigation of selective inhibitory activity of chromone-based compounds against monoamine oxidase (MAO)-A and -B

Monoamine oxidase (MAO) is crucial for the breakdown of monoamine neurotransmitters, making it a promising target for treating neurodegenerative disorders, such as depression, Alzheimer’s disease, and Parkinson’s disease. In this study, we investigated the selective inhibitory activity of chromone-based compounds against MAO-A and MAO-B for neurodegenerative disease treatment. In literary sources, thirty chromone derivatives have been identified as potential ligands for MAO-A and MAO-B inhibitors. We utilized molecular docking to evaluate how the most active compound interacted with the targeted MAO-A and MAO-B. Compound 2 g, the most active for MAO-A, demonstrated a lower CDOCKER energy compared to the co-crystallized ligand. Meanwhile, compound 2f, the most active for MAO-B, showed a CDOCKER energy similar to the co-crystallized ligand and exhibited similar binding patterns. Furthermore, we constructed a quantitative structure-activity relationship (QSAR) model to predict the properties and estimate IC50 values for 30 chromone derivatives functioning as MAO-A and MAO-B inhibitors. The model predictions were validated against experimental measurements. Our 2D QSAR model demonstrated robustness, with a statistically significant non-cross-validated coefficient (r2 < 0.9), cross-validated correlation coefficient (q2 < 0.6), and predictive squared correlation coefficient (r2 pred < 0.8). Additionally, MD simulations confirmed the stable binding of compounds 2 g and 2f with MAO-A and MAO-B, respectively, displaying substantial binding energy. The most effective pharmacophore model identified key features, such as hydrogen bond acceptors and hydrophobic interactions, that contribute significantly to inhibitory potency. This study offers valuable insight into the selection of compounds with improved selectivity for MAO inhibition.

New 2-hydrazinothiazole derivatives as potential MAO-A, MAO-B, AChE, and BChE inhibitors

The incidence of neurodegenerative Alzheimer’s and Parkinson’s diseases is increasing worldwide every day, and treatment options are currently very limited. There is no definitive cure for these diseases, and the drugs available in clinical practice only provide symptomatic relief without halting the progression of neurodegeneration. One commonly employed strategy in the treatment of Alzheimer’s and Parkinson’s diseases is to return neurotransmitter levels by inhibiting enzymes like cholinesterase (ChE) and monoamine oxidase (MAO). In this research, we focused on investigating the therapeutic potential of 2-[2-(substituted benzylidene)hydrazinyl]-4-(substituted phenyl)thiazole derivatives (2a–2h) by incorporating hydrazine, known for its inhibitory effects on monoamine oxidases, into the structure of molecules that inhibit acetylcholinesterase. Thiazole ring was included in these derivatives due to its reported inhibitory activity against both cholinesterases and monoamine oxidase enzymes. When the enzyme inhibition activities were evaluated, it was determined that compounds 2c, 2d, and 2h showed the highest inhibitory activity against AChE, while compounds 2f and 2h expressed the highest activity against MAO-B. It was determined that compound 2h had the highest inhibitory activity on both AChE (0.030 ± 0.001 μM) and MAO-B (0.048 ± 0.002 μM) and compound 2h was the only compound with conspicuous dual inhibitory activity. Furthermore, molecular docking calculations and molecular dynamics simulations were found to agree with experimental results.

Design, synthesis and evaluation of benzothiazole-derived phenyl thioacetamides as dual inhibitors of monoamine oxidases and cholinesterases.

A series of rationally designed benzothiazole-derived thioacetamides was synthesized and investigated for monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) inhibition properties. The tested compounds 18-31 inhibited MAO-A and MAO-B in the micromolar to nanomolar range and AChE in the submicromolar range. Compound 28 was identified as the most potent MAO-A inhibitor with an IC50 = 0.030 ± 0.008 µM, whereas compound 30 showed the highest potency towards MAO-B and AChE with IC50 values of 0.015 ± 0.007 µM and 0.114 ± 0.003 µM, respectively. Further, compound 30 inhibited BChE at an IC50 value of 4.125 ± 0.143 µM. Among all screened molecules, compound 30 emerged as the lead dual MAO-B and AChE inhibitor that blocked these enzymes in a competitive-reversible and mixed-reversible mode, respectively. Selected compounds have displayed iron-chelation and antioxidant properties. Further, computational assessment of ligand binding affinity and pharmacokinetic parameters of all new compounds and molecular dynamic simulation of compound 30 with MAO-B and AChE were carried out to understand ligand efficiency, pharmacokinetic, and virtual molecular interaction profile, respectively. The in silico ADMET prediction studies revealed a few undesired pharmacokinetic attributes of our compounds. The attempted virtual lead-based library synthesis and subsequent biological investigation produced a new benzothiazole-bearing dual MAO-B and AChE inhibitor as a prospective MTDL candidate for treating neurological disorders.

Neuroprotective Effect of Natural Indole and β-carboline Alkaloids against Parkinson's Disease: An Overview.

Parkinson's disease (PD) is a devastating neurodegenerative condition that mostly damages dopaminergic neurons in the substantia nigra and impairs human motor function. Males are more likely than females to have PD. There are two main pathways associated with PD: one involves the misfolding of α-synuclein, which causes neurodegeneration, and the other is the catalytic oxidation of dopamine via MAO-B, which produces hydrogen peroxide that can cause mitochondrial damage. Parkin (PRKN), α-synuclein (SNCA), heat shock protein (HSP), and leucine-rich repeat kinase-2 (LRRK2) are some of the target areas for genetic alterations that cause neurodegeneration in Parkinson's disease (PD). Under the impact of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is also important in Parkinson's disease (PD), inhibition of mitochondrial complex 1 results in enhanced ROS generation in neuronal cells. Natural products are still a superior option in the age of synthetic pharmaceuticals because of their lower toxicity and moderate side effects. A promising treatment for PD has been discovered using beta-carboline (also known as " β-carboline") and indole alkaloids. However, there are not many studies done on this particular topic. In the herbs containing β-carbolines and indoles, the secondary metabolites and alkaloids, β-carbolines and indoles, have shown neuroprotective and cognitive-enhancing properties. In this review, we have presented results from 18 years of research on the effects of indole and β-carboline alkaloids against oxidative stress and MAO inhibition, two key targets in PD. In the SAR analysis, the activity has been correlated with their unique structural characteristics. This study will undoubtedly aid researchers in looking for new PD treatment options.

Evaluation of Rhus Tox, a homeopathic formulation for treatment of Parkinson’s and Alzheimer’s disease: a network pharmacology and ex-vivo approach

Rhus toxicodendron, commonly known as Rhus tox, is a potent homeopathic medication widely used in the treatment of rheumatoid arthritis and is claimed to have potential benefits for neurodegenerative disorders. Given the ability of homeopathic medications to address the root causes of diseases, our study aimed to evaluate Rhus tox for Parkinson’s Disease (PD) and Alzheimer’s Disease (AD) using in-silico, ex-vivo, and network pharmacology approaches to obtain comprehensive information on its multi-component and multi-target effects. Phytoconstituents of Rhus tox were collected from PubMed and screened for ADMET properties. Targets for these constituents were predicted using the Binding Database and DisGeNET, resulting in 61 targets for Parkinsonism and 85 targets for alzhiemer’s disease. Protein-protein interactions (PPIs) were analysed using the STRING database. A Venn diagram was constructed for all these targets, and 5 out of 13 common targets were selected for docking studies. From these analyses, kaempferol and quercetin were identified as promising neuroprotective agents with good blood-brain barrier (BBB) permeation. The docking studies validated these predictions as most of the constituents showed good binding affinity with EGFR, SNCA and MAO-B. It was further validated using MAO inhibition assay, in which Quercetin was found to be highly efficacious, with an IC50 value of 32.69 μg/mL among the other flavonoids studied for MAO inhibition assay. The Rhus Tox also showed MAO inhibition assay similar to the standard seligiline. To conclude, we can propose that Rhus Tox primarily acts on the dopaminergic pathway, serotonergic pathway, and EGFR signaling pathway. Further in vitro and in vivo studies are needed to confirm the mechanism action and efficacy of Rhus Tox for treatment of neurodegenerative diseases.

Driving Abilities and Wearing-Off in Parkinson's Disease: A Driving Simulation Study.

Driving abilities require the synchronized activity of cerebral networks associated with sensorimotor integration, motricity, and executive functions. Drivers with Parkinson's disease (DwP) have impaired driving ability, but little is known about the impact of "wearing-off" and therapies in addition to L-DOPA on driving capacities. This study aimed to (i) compare driving performance between DwP during different motor states and healthy controls and (ii) assess the impact of add-on therapies on driving abilities. DwP (n = 26) were enrolled as individuals experiencing wearing-off symptoms and treated (within 6 months before the enrollment) with add-on therapies to L-DOPA, including MAO inhibitors for DwP-A (n = 12) or opicapone for DwP-B (n = 14). Age- and sex-matched controls (CON, n = 12) were also enrolled. DwP received two driving assessments in a driving simulator during their "best-on" time and during their wearing-off time on different days. An anamnestic driving questionnaire was collected with the assistance of partners. A Virtual Driving Rating Scale (VDRS) was calculated, as well as learning curves (LCs) for driving items calculated in minutes. DwP reported worse driving performance than CON at the driving questionnaire. In line with this, DwP showed worse VDRS (p < 0.01) and LC (p = 0.021) than CON. Lower VDRS was associated with wearing-off (p < 0.01), but DwP-B had better driving performance while in their "best-on" time (p = 0.037) and more items improving with LCs (7 vs. 3) than DwP-A. DwP demonstrated impaired driving compared to controls. Wearing-off symptoms can also affect driving ability, but therapies (opicapone more so than MAO inhibitors) may play a role in preserving specific driving skills, possibly through maintaining learning abilities.

MAO-A Inhibitor Properties by Molecular Modeling Method, Antimicrobial Activity and Characterization of Silver Nanoparticles Synthesized from Lactifluus Bertillonii Mushroom

This work focuses on the antimicrobial activity of AgNPs produced using a green, environmentally friendly synthesis process from Lactifluus bertillonii mushrooms using the minimum inhibitory concentration (MIC) method. Additionally, the inhibitory characteristics of the chemicals present in the mushroom extract are also determined. SEM, TEM, UV-vis, and FT-IR instruments are employed as part of the study. The average particle size in the characterisation was determined by the imaging program to be 10.471 nm. Additionally, the activity of AgNPs against Klebsiella pneumoniae was found to be 512 µg/ml in the antimicrobial activity tests carried out using the MIC method, which yields more sensitive results. The target enzyme for treating depression, the MAO-A enzyme, whose 2Z5X coding structure was derived from humans, was employed in docking research. The three dimensional structures of Isoquercitrin (-8.2 kcal/mol), Rutin (-9.3 kcal/mol), Fisetin (-8.2 kcal/mol), Chrysin (-9.4 kcal/mol), Quercetin (-10.6 kcal/mol), Naringenin (8.8 kcal/mol), Kaemferol (-10.8 kcal/mol) and Luteolin (-10.8 kcal/mol) were optimized in the Gaussian09 program using the DFT/B3LYP/6-31G(d,p) basis set. Then, binding energies of these structures were determined with the help of the AutoDock Vina software. Their binding energies have been shown to indicate that they possess the property of MAO-A inhibitors.

Design, synthesis, in vitro, and in silico study of benzothiazole-based compounds as a potent anti-Alzheimer agent.

Alzheimer's disease (AD) is a multifactorial neurological disorder that involves multiple enzymes in the process of developing. Conventional monotherapies provide relief, necessitating alternative multi-targeting approaches to address AD complexity. Therefore, we synthesize N-(benzo[d]thiazol-2-yl) benzamide-based compounds and tested against monoamine oxidases (MAO-A and MAO-B). In the in vitro experimental evaluation of MAO, all the compounds displayed remarkable potency, having IC50 values in the lower micromolar range. The most potent MAO-A inhibitor was (3e) with an IC50 value of 0.92 ± 0.09μM, whereas, (3d) was the most potent inhibitor of MAO-B with an IC50 value of 0.48 ± 0.04μM. Moreover, Enzyme kinetics studies revealed that the potent inhibitors of MAO-A and MAO-B showed competitive mode of inhibition. Furthermore, molecular docking studies were also performed to confirm the mode of inhibition and obtain an intuitive picture of potent inhibitors. It also revealed several important interactions, particularly hydrogen bonding interaction. All the newly synthesized compounds showed good ADME pharmacokinetic profile and followed Lipinski rule; these compounds represent promising hits for the development of promising lead compounds for AD treatment.

Docking, Synthesis, and In vitro Anti-depressant Activity of Certain Isatin Derivatives.

In vitro, the molecular docking method has been suggested for estimating the biological affinity of the pharmacophores with physiologically active compounds. It is the latter stage in molecular docking, and the docking scores are examined using the AutoDock 4.2 tool program. The chosen compounds can be evaluated for in vitro activity based on the binding scores, and the IC50 values can be computed. The purpose of this work was to create methyl isatin compounds as potential antidepressants, compute physicochemical characteristics, and carry out docking analysis. The protein data bank of the RCSB (Research Collaboratory for Structural Bioinformatics) was used to download the PDB structures of monoamine oxidase (PDB ID: 2BXR) and indoleamine 2,3-dioxygenase (PDB ID: 6E35). Based on the literature, methyl isatin derivatives were chosen as the lead chemicals. By determining their IC50 values, the chosen compounds were tested for in vitro anti-depressant activity. The binding scores for the interactions of SDI 1 and SD 2 with indoleamine 2,3 dioxygenase were found to be -10.55 kcal/mol and -11.08 kcal/mol, respectively, while the scores for their interactions with monoamine oxidase were found to be -8.76 kcal/mol and -9.28 kcal/mol, respectively, using AutoDock 4.2. The relationship between biological affinity and pharmacophore electrical structure was examined using the docking technique. The chosen compounds were tested for their ability to inhibit MAO, and the IC50 values for each were found to be 51.20 and 56, respectively. This investigation has identified many novel and effective MAO-A inhibitors from the family of chemicals known as methyl isatin derivatives. Lead optimization was applied to the SDI 1 and SDI 2 derivatives. The superior bioactivity, pharmacokinetic profile, BBB penetration, pre-ADMET profiles, such as HIA (human intestinal absorption) and MDCK (Madin-Darby canine kidney), plasma protein binding, toxicity assessment, and docking outcomes, have been obtained. According to the study, synthesised isatin 1 and SDI 2 derivatives exhibited a stronger MAO inhibitory activity and effective binding energy, which may help prevent stress-induced depression and other neurodegenerative disorders caused by a monoamine imbalance.

Molecular Mechanism and Structure-activity Relationship of the Inhibition Effect between Monoamine Oxidase and Selegiline Analogues.

To investigate the inhibition properties and structure-activity relationship between monoamine oxidase (MAO) and selected monoamine oxidase inhibitors (MAOIs, including selegiline, rasagiline and clorgiline). The inhibition effect and molecular mechanism between MAO and MAOIs were identified via the half maximal inhibitory concentration (IC50) and molecular docking technology. It was indicated that selegiline and rasagiline were MAO B inhibitors, but clorgiline was MAO-A inhibitor based on the selectivity index (SI) of MAOIs (0.000264, 0.0197 and 14607.143 for selegiline, rasagiline and clorgiline, respectively). The high-frequency amino acid residues of the MAOIs and MAO were Ser24, Arg51, Tyr69 and Tyr407 for MAO-A and Arg42 and Tyr435 for MAO B. The MAOIs and MAO A/B pharmacophores included the aromatic core, hydrogen bond acceptor, hydrogen bond donor-acceptor and hydrophobic core. This study shows the inhibition effect and molecular mechanism between MAO and MAOIs and provides valuable findings on the design and treatment of Alzheimer's and Parkinson's diseases.

Evaluation of Anti-Depressant Potential of Standardized Hydroethanolic Extract of S. barbata D. Don Using Chronic Unpredictable Mild Stress Model

Background: S. barbata D. Don is a Chinese herb, that belongs to the family Lami-aceae. It has established traditional use in ethnomedicine for treating various ailments, includ-ing mood disorders and sleep disorders, which led to growing interest in exploring its neuro-logical potential, particularly as a potential anti-depressant agent. Aims: This study explores the anti-depressant potential of the HSBE utilizing a Chronic Un-predictable Mild Stress-induced depression model in mice. Additionally, the research aims to elucidate the underlying mechanisms of action. Methods: Swiss albino mice were subjected to a 3-week CUMS paradigm and subsequently administered HSBE at doses of 200 and 400 mg/kg via oral administration. The behavioral alterations were evaluated using the FST, TST, OFT, and SPT. Brain levels of serotonin, dopa-mine, and nor-epinephrine were estimated in different brain regions (cortex, hippocampus, and hypothalamus) to uncover the molecular mechanism. Additionally, assays for monoamine oxi-dase-A, monoamine oxidase-B, and antioxidant enzyme activities were conducted. Plasma ni-trite and corticosterone levels were also measured to get further insight into potential mecha-nisms underlying the anti-depressant effects of HSBE. Results: HSBE significantly ameliorated depressive-like behavior induced by CUMS para-digm, as evidenced by reduced immobility in FST and TST, increased locomotor activity in OFT, and improved sucrose preference in SPT. Neurochemical analysis revealed a significant increase in serotonin, dopamine, and norepinephrine levels in the cortex, hippocampus, and hypothalamus of HSBE-treated mice, implying a potential regulation of monoaminergic neuro-transmitter levels. Moreover, biochemical analyses demonstrated a significant inhibition of both MAO-A and MAO-B activity, contributing to the increase of the brain levels of neuro-transmitters. The administration of HSBE also led to a significant enhancement of antioxidant enzyme activities and reduced brain lipid peroxidation, indicating a pronounced antioxidant effect of HSBE. Furthermore, decreased plasma nitrite and corticosterone levels provided ad-ditional insights into HSBE's potential multi-targeted anti-depressant mechanism. Conclusion: This study indicates that HSBE exhibits robust anti-depressant properties, sup-ported by behavioral, neurochemical, and biochemical alterations. These findings underscore the therapeutic promise of HSBE as a natural intervention for depressive disorders, warranting further clinical exploration.

Exploring Chroman‐4‐One Derivatives as MAO‐B Inhibitors: A Comprehensive Computational Study

AbstractThe enzyme monoamine oxidase‐B (MAO‐B) significantly affects the neurotransmitter's metabolism, including norepinephrine, dopamine, and serotonin. Alzheimer's disease is the result of the dysregulation of MAO‐B activity, which is also attached to another neurological disorder, that is, Parkinson's disease. The MAO‐B antagonists are now seen as potential therapeutics for these conditions. A promising approach for improving the effectiveness of novel MAO inhibitors is using chromanone scaffolds. In this work, we used a multimodal computational approach to assess the inhibitory effects of chroman‐4‐one derivatives on MAO‐B. The study utilized molecular docking methodologies to investigate and evaluate the intricate binding interactions between MAO‐B and chroman‐4‐one derivatives. Moreover, the ADME study provided insightful information about the pharmacokinetic characteristics of chroman‐4‐one derivatives. The analysis of the temporal stability and dynamic behavior of ligand‐protein interactions has benefited from the application of MD simulations. To determine the binding free energies and gain a deeper comprehension of the binding affinity between chroman‐4‐one derivatives and MAO‐B, MM‐PBSA calculations were also performed. This study offers valuable information about logical design and the optimization of MAO‐B antagonists and highlights the potential of computational techniques in speeding up the drug discovery process.

Exploring Novel Quinoline-1,3,4-Oxadiazole Derivatives for Alzheimer's Disease: Their Design, Synthesis, and In-Vitro and In-Silico Investigations.

Alzheimer's Disease (AD) is a complicated and advanced neurodegenerative condition accompanied by gradual cholinergic neuronal death and higher levels of monoamine oxidase-B (MAO-B) enzyme. In this study, a series of novel hybrid compounds combining 1,3,4-oxadiazole and quinoline moieties were synthesized and evaluated for their potential as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and MAO enzymes. The chemical structures of the synthesized compounds were confirmed using various analytical techniques, such as mass spectrometry, infrared spectroscopy (IR), proton nuclear magnetic resonance (1H-NMR), and carbon and nuclear magnetic resonance (13C-NMR). The final products were evaluated for anticholinesterase potential by applying modified Ellman's spectrometric method, whereas a fluorometric method was used to assess MAO inhibition properties. In-silico studies using molecular docking and molecular dynamics simulation (MDS) methods has been also conducted. Among the synthesized compounds, 5a, 5c, and 6a demonstrated substantial activity against AChE, with IC50 values of 0.033 μM, 0.096 μM, and 0.177 μM, respectively. A molecular docking study was performed to elucidate the binding modes and establish the structure-activity relationship (SAR) of the most active compounds (5a, 5c, and 6a). Molecular dynamics simulation (MDS) of the most potent compound, 5a, was also conducted to examine the stability of the interactions with the receptor. Moreover, the physicochemical properties of the active products were also studied. Overall, this research contributes to the development of 1,3,4-oxadiazole- quinoline hybrids as potential AChE inhibitors for the treatment of Alzheimer's disease.

Inhibition of monoamine oxidases and neuroprotective effects: chalcones vs. chromones.

Eighteen compounds derived from two sub-series, (HC1-HC9) and (HF1-HF9), were synthesized and evaluated for their inhibitory activities against monoamine oxidase (MAO). HC (chalcone) series showed higher inhibitory activity against MAO-B than against MAO-A, whereas the HF (chromone) series showed reversed inhibitory activity. Compound HC4 most potently inhibited MAO-B with an IC50 value of 0.040μM, followed by HC3 (IC50 = 0.049μM), while compound HF4 most potently inhibited MAO-A (IC50 = 0.046μM), followed by HF2 (IC50 = 0.075μM). The selectivity index (SI) values of HC4 and HF4 were 50.40 and 0.59, respectively. Structurally, HC4 (4-OC2H5 in B-ring) showed higher MAO-B inhibition than other derivatives, suggesting that the -OC2H5 substitution of the 4-position in the B-ring contributes to the increase of MAO-B inhibition, especially -OC2H5 (HC4) > -OCH3 (HC3) > -F (HC7) > -CH3 (HC2) > -Br (HC8) > -H (HC1) in order. In MAO-A inhibition, the substituent 4-OC2H5 in the B-ring of HF4 contributed to an increase in inhibitory activity, followed by -CH3 (HF2), -F (HF7), -Br (HF8), -OCH3 (HF3), and-H (HF1). In the enzyme kinetics and reversibility study, the Ki value of HC4 for MAO-B was 0.035 ± 0.005μM, and that of HF4 for MAO-A was 0.035 ± 0.005μM, and both were reversible competitive inhibitors. We confirmed that HC4 and HF4 significantly ameliorated rotenone-induced neurotoxicity, as evidenced by the reactive oxygen species and superoxide dismutase assays. This study also supports the significant effect of HC4 and HF4 on mitochondrial membrane potential in rotenone-induced toxicity. A lead molecule was used for molecular docking and dynamic simulation studies. These results show that HC4 is a potent selective MAO-B inhibitor and HF4 is a potent MAO-A inhibitor, suggesting that both compounds can be used as treatment agents for neurological disorders.

Unveiling the Intricacies of Monoamine Oxidase-A (MAO-A) Inhibition in Colorectal Cancer: Computational Systems Biology, Expression Patterns, and the Anticancer Therapeutic Potential.

Colorectal cancer (CRC) remains a significant health burden globally, necessitating a deeper understanding of its molecular intricacies for effective therapeutic interventions. Elevated monoamine oxidase-A (MAO-A) expression has been consistently observed in CRC tissues, correlating with advanced disease stages and a poorer prognosis. This research explores the systems biology effects of MAO-A inhibition with small molecule inhibitor clorgyline regarding CRC. The applied systems biology approach starts with a chemocentric informatics approach to derive high-confidence hypotheses regarding the antiproliferative effects of MAO-A inhibitors and ends with experimental validation. Our computational results emphasized the anticancer effects of MAO-A inhibition and the chemogenomics similarities between clorgyline and structurally diverse groups of apoptosis inducers in addition to highlighting apoptotic, DNA-damage, and microRNAs in cancer pathways. Experimental validation results revealed that MAO inhibition results in antiproliferative antimigratory activities in addition to synergistic effects with doxorubicin. Moreover, the results demonstrated a putative role of MAO-A inhibition in commencing CRC cellular death by potentially mediating the induction of apoptosis.

Synthesis and evaluation of 2-methylbenzothiazole derivatives as monoamine oxidase inhibitors

AbstractNeurodegenerative disorders are caused by the progressive death of neuronal cells in specific regions of the brain and spinal cord. The most common neurodegenerative disorders are Alzheimer’s disease and Parkinson’s disease. The inhibition of enzymes that metabolise neurotransmitter amines is an important approach in the treatment of these disorders and monoamine oxidase (MAO) B inhibitors have thus been used for the treatment of Parkinson’s disease. Inhibitors of the MAO-A isoform, in turn, are used clinically for the treatment of affective (e.g., major depression) and anxiety disorders. Recent studies have shown that benzothiazole derivatives act as potent MAO inhibitors. Based on these findings, the present study group synthesised thirteen 2-methylbenzo[d]thiazole derivatives and evaluated their in vitro MAO inhibition properties. The results showed that the benzothiazole derivatives were potent and selective inhibitors of human MAO-B, with all compounds exhibiting IC50 values &lt; 0.017 µM. The most potent MAO-B inhibitor (4d) had an IC50 value of 0.0046 µM, while the most potent MAO-A inhibitor (5e) had an IC50 value of 0.132 µM. It may be concluded that active benzothiazole derivatives may serve as potential leads for the development of MAO inhibitors for the treatment of neuropsychiatric and neurodegenerative disorders.

Synthesis, biochemistry, and in silico investigations of isatin-based hydrazone derivatives as monoamine oxidase inhibitors

Ten isatin-based hydrazone derivatives were synthesized using two subseries, IA (isatin + acetophenone) and IB (isatin + benzaldehyde), and evaluated for their monoamine oxidases (MAOs) inhibitory activity. All the compounds showed stronger MAO-A inhibition than MAO-B, and the IB series showed more effective MAO-A inhibitory activity than IA series. Compound IB4 most potently inhibited MAO-A (half maximal inhibitory concentration IC50 = 0.015 µM), followed by IB3 (IC50 = 0.019 µM). On the contrary, compound IB3 showed the highest MAO-B inhibition (IC50 = 0.068 µM), followed by IB4 (IC50 = 1.87 µM). Compound IB3 and IB4 had low selectivity indices of 3.68 and 8.50, respectively. Structurally, the methyl group of IA series decreased the inhibition of both MAO-A and MAO-B. Among them, IB3 and IB4 (4-Cl and 4-Br in B-ring, respectively) showed higher MAO-A and MAO-B inhibition than the other substitutions. Inhibition constant Ki values of IB3 and IB4 for MAO-A were 0.0088 and 0.0063 µM, respectively, and those for MAO-B were 0.048 and 0.060 µM, respectively. IB3 and IB4 were competitive, reversible inhibitors of MAO-A and MAO-B. Molecular docking analysis predicted that IB3 and IB4 formed stable hydrogen bonds between Asn181 and the NH atom of isatin in the ligand-protein complex. Dynamic analysis revealed that IB3 and IB4 are stable with both MAO isoforms. These observations suggest IB3 and IB4 are potent and reversible MAO-A and MAO-B inhibitors and both compounds can be used as therapeutic agents for neurological disorders.

A Comprehensive Review of The Molecular Dynamic Study Of Chalcones, Coumarins and Chromones as Selective MAO‐B Inhibitors [2015‐Till Date

AbstractMolecular dynamics (MD) simulation is an in silico method used in the biomolecular level of research to study how the protein interacts with the target with time. It provides a detailed information of the protein dynamics and ligand structure with the crucial amino acid interactions. Monoamine oxidase B (MAO−B) is a crucial isoenzyme responsible for the catalyses of oxidative deamination of various biogenic amines in the brain and peripheral tissues. The selective inhibitors of MAO−B are considered as the management of symptoms of neurodegenerative disorders like Alzheimer's disease(AD) and Parkinson disease(PD). Recently the structural scaffolds containing chalcones, coumarins and chromones derived candidates shown potent, selective, competitive and reversible type of MAO−B inhibitors. The structural similarities between the above scaffolds can produce almost similar type of interactions in the inhibitor binding cavity of MAO−B. Numerous molecular simulation reports were supported by the above mentioned fact. The current review focus on the last ten year molecular dynamics report of chalcones, coumarins and chromones towards MAO−B inhibition. The review also focuses on the software details used in the MD dynamics simulation and the structural requirement from each class of compound for the recognition of MAO−B inhibitory activity.

Inhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivatives.

Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson's disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 μM, followed by S16 (IC50 = 0.979 μM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 μM, followed by S5 (IC50 = 3.857 μM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH3 > -F > -CN > -CH3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the Ki values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 μM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood-brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi-pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.

Investigation of 3-Phenylcoumarin Derivatives as Potential Multi-target Inhibitors for Human Cholinesterases and Monoamine oxidases: A Computational Approach.

Alzheimer's disease (AD) is the predominant etiology of dementia, impacting a global population of approximately 50 million individuals. In the field of medicinal chemistry, there have been notable advancements in the utilization of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors for the purpose of addressing the neurotransmitter shortage associated with Alzheimer's disease (AD). A selection of previously synthesized 3-Phenylcoumarin derivatives (5a-m) were selected for examination in the pursuit of potential multi-targeting inhibitors of MAO-A, MAO-B, AChE, and BChE. The stability and reactivity of the compounds were investigated through the utilization of density functional theory (DFT) simulations. Subsequently, a CoMFA technique, grounded in 3D-QSAR principles, was employed to construct a model and predict the inhibitory properties of analogues belonging to the class of 3-phenylcoumarin derivatives. Through the application of molecular docking methodologies, we have employed predictive analyses to determine the potential binding interactions and stability of the drugs under investigation. The results obtained from the present investigation indicate that the 3-phenylcoumarin derivatives possess a reactive electronic characteristic that is crucial for their anti-cholinesterase activity. Compound 5a demonstrated a noteworthy binding score with AChE, BChE, MAO-A and MAO-B, respectively, indicating a robust binding affinity.