MAO Inhibitors Research Articles

Total Synthesis and Monoamine Oxidase Inhibitory Activities of (±)-Entonalactam A and Its Derivatives.

The first total synthesis of isoindolinone (±)-entonalactam A (6), originally obtained from the fungus Entonaema sp., was achieved in 14 steps from commercially available 5-bromovanillin via benzophenone intermediates. Isoindolinone, phthalide, and benzophenone analogues of natural products were also synthesized. The monoamine oxidase (MAO) A and B inhibitory activities were tested. The isoindolinone derivative 30 exhibited inhibition of both MAO-A and -B (IC50 = 17.8 and 15.8 μM, respectively).

Biological activity evaluation of novel monoamine oxidase inhibitory compounds targeting Parkinsondisease.

Aim: Design of 5-methoxy benzofuran hybrids with 2-carbohydrazide and 2-(1,3,4-oxadiazol-2-yl) as potential inhibitors of monoamine oxidase (MAO)-B targeting Parkinson disease. Materials and methods: 12compounds were synthesized and analyzed via high-resolution mass spectrometry, 1H nuclear magnetic resonance and 13C nuclear magnetic resonance techniques. In vitro fluorometric assay was used to investigate the activity of the synthesized compounds on both MAO-A and MAO-B isozymes. Results: Three compounds - 3a, 3c and 3e - displayed half maximal inhibitory concentration values of 0.051±0.002, 0.038±0.001 and 0.077±0.003μM in the inhibition of MAO-A and 0.048±0.002, 0.040±0.001 and 0.072±0.002μM for MAO-B, respectively. A molecular dynamics simulation study showed that compound 3c has poor stability as a complex with MAO-A. Conclusion: Compound 3c may be a potential candidate for the treatment of Parkinson disease.

The inhibition of monoamine oxidase by 2H-1,4-benzothiazin-3(4H)-ones

Monoamine oxidase (MAO) plays an important role in psychiatric and neurological disorders, such as depression and Parkinson's disease. As a result, MAO represents a key target for developing drugs to treat these conditions. The present study aimed to synthesise and discover compounds that inhibit the MAO enzymes and which may be relevant to the treatment of neurological disorders. A series of nine 2H-1,4-benzothiazin-3(4H)-ones were synthesised and evaluated as potential in vitro inhibitors of human MAO-A and MAO-B. The benzothiazinones bear structural similarity to a series of 3,4-dihydro-2(1H)-quinolinones that have been shown to be highly potent MAO-B inhibitors. The results show that the benzothiazinones inhibit both MAO isoforms but are more potent MAO-B inhibitors. The most potent inhibitors exhibit IC50 values of 0.0027 (1b), 0.0082 (1c), 0.0096 (1d), and 0.0041 µM (1h) for MAO-B, and 0.714 µM (1d) for MAO-A. These benzothiazinone derivatives exhibit promising MAO inhibition activities and may be developed into clinically useful agents for the treatment of Parkinson’s disease. Interestingly, related 4H-3,1-benzothiazin-4-ones have previously been investigated as dual-target-directed drugs that inhibit MAO-B and antagonize adenosine A2A receptors for the treatment of Parkinson’s disease. Based on an interest in d-amino acid oxidase (DAAO) as a target for the treatment for schizophrenia, the 2H-1,4-benzothiazin-3(4H)-ones were also evaluated as in vitro inhibitors of this enzyme. Among the study compounds, only 7-hydroxy-2H-1,4-benzothiazin-3(4H)-one (IC50 = 4.20 µM) was an active DAAO inhibitor. Finally, molecular docking was employed to gain insight into the binding modes and interactions of the 2H-1,4-benzothiazin-3(4H)-ones with MAO.

Monoamine Oxidase Inhibitors Prevent Glucose-Dependent Energy Production, Proliferation and Migration of Bladder Carcinoma Cells.

Bladder cancer is the 10th most common cancer in the world and has a high risk of recurrence and metastasis. In order to sustain high energetic needs, cancer cells undergo complex metabolic adaptations, such as a switch toward aerobic glycolysis, that can be exploited therapeutically. Reactive oxygen species (ROS) act as key regulators of cancer metabolic reprogramming and tumorigenesis, but the sources of ROS remain unidentified. Monoamine oxidases (MAOs) are mitochondrial enzymes that generate H2O2 during the breakdown of catecholamines and serotonin. These enzymes are particularly important in neurological disorders, but recently, a new link between MAOs and cancer has been uncovered, involving their production of ROS. At present, the putative role of MAOs in bladder cancer has never been evaluated. We observed that human urothelial tumor explants and the bladder cancer cell line AY27 expressed both MAO-A and MAO-B isoforms. Selective inhibition of MAO-A or MAO-B limited mitochondrial ROS accumulation, cell cycle progression and proliferation of bladder cancer cells, while only MAO-A inhibition prevented cell motility. To test whether ROS contributed to MAO-induced tumorigenesis, we used a mutated form of MAO-A which was unable to produce H2O2. Adenoviral transduction of the WT MAO-A stimulated the proliferation and migration of AY27 cells while the Lys305Met MAO-A mutant was inactive. This was consistent with the fact that the antioxidant Trolox strongly impaired proliferation and cell cycle progression. Most interestingly, AY27 cells were highly dependent on glucose metabolism to sustain their growth, and MAO inhibitors potently reduced glycolysis and oxidative phosphorylation, due to pyruvate depletion. Accordingly, MAO inhibitors decreased the expression of proteins involved in glucose transport (GLUT1) and transformation (HK2). In conclusion, urothelial cancer cells are characterized by a metabolic shift toward glucose-dependent metabolism, which is important for cell growth and is under the regulation of MAO-dependent oxidative stress.

Development of MAO-A and 5-HT2AR Dual Inhibitors with Improved Antidepressant Activity.

Designing dual-target inhibitors targeting 5-HT2AR and MAO-A could synergistically promote interstitial 5-HT levels, so as to exhibit a more efficient antidepressant effect. On the premise of maintaining the original pharmacophore binding, arylpiperazine scaffolds and 5-oxygen-substituted oxoisoaporphines were hybridized to afford 15 dual-target inhibitors through suitable linkers. Among all inhibitors, I14 exhibited the best inhibitory activities against 5-HT2AR and MAO-A. In vitro cell proliferation assays showed that most compounds were nontoxic to neuronal cells and normal hepatocytes. I14 also significantly ameliorated the depression-like behavior of zebrafish and mice. Further study revealed that I14 was able to occupy the active cavity of 5-HT2AR and MAO-A with multiple hydrogen bonding forces and π-π stacking interaction. I14 was also able to repair the damage of mice hippocampal neuronal cells and reduce the expression of 5-HT2AR in mice brain tissue. In conclusion, I14 could be a potential antidepressant candidate for further study.

Hansch-Type QSAR Models for the Rational Design of MAO Inhibitors: Basic Principles and Methodology.

Hansch-type regression analysis enables the derivation of quantitative structure-activity relationship (QSAR) equations correlating bioactivity data with physicochemical parameters accounting for hydrophobicity, electronic properties, and steric effects of molecules or functional groups (substituents). Two datasets of MAO A and B inhibitors were enrolled in prototypical workflows employing multiparametric stepwise regression analysis, which includes linear and nonlinear (generally quadratic) terms. The optimal choice of variables (and/or combinations thereof) along with statistical validation yielded two robust equations describing MAO B potency and B/A selectivity, which included three and one parameter(s), respectively, and explained more than 80% of y-variance (r2) with low standard deviation (s) and good statistical significance (F, Fisher value).

Isatoic anhydrides as novel inhibitors of monoamine oxidase

The monoamine oxidase (MAO) enzymes metabolise neurotransmitter amines in the central and peripheral tissues, and thereby contribute to the regulation of neurotransmission. Inhibitors of MAO modulate the levels of neurotransmitters in the central nervous system, and have been used for several decades for the treatment of depression and Parkinson’s disease, while potential new therapeutic applications in other diseases such as prostate cancer and heart failure may exist. In the interest of discovering new classes of chemical compounds that potently inhibit the MAOs, the present study synthesises a series of ten isatoic anhydrides and evaluates their potential as in vitro inhibitors of human MAO-A and MAO-B. The isatoic anhydrides bear structural similarity to a series of 3,4-dihydro-2(1H)-quinolinones as well as to series of isatins and phthalimides that have been reported to act as potent MAO-B inhibitors. The results document that the isatoic anhydrides inhibit both MAO isoforms with the most potent inhibitors exhibiting IC50 values of 0.010 µM (1b and 1h) and 0.0047 µM (1j) for MAO-A and MAO-B, respectively. Molecular docking suggests that isatoic anhydrides exhibit similar binding modes and interactions with MAO-A and MAO-B, which may explain their potent inhibition of both isoforms. It may be concluded that the isatoic anhydrides represent a new class of MAO inhibitors, while it is interesting to note that very few studies on the pharmacological actions of isatoic anhydrides have been reported. As a secondary aim, the isatoic anhydrides were also evaluated as potential inhibitors of d-amino acid oxidase (DAAO), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).

Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities

Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 µM; hBChE: IC50 = 0.093 ± 0.003 µM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 µM; IC50 (hBChE) = 0.659 ± 0.077 µM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.

Phytoestrogen Coumestrol Selectively Inhibits Monoamine Oxidase-A and Amyloid β Self-Aggregation.

Pueraria lobata leaves contain a variety of phytoestrogens, including flavonoids, isoflavonoids, and coumestan derivatives. In this study, we aimed to identify the active ingredients of P. lobata leaves and to elucidate their function in monoamine oxidase (MAO) activation and Aβ self-aggregation using in vitro and in silico approaches. To the best of our knowledge, this is the first study to elucidate coumestrol as a selective and competitive MAO-A inhibitor. We identified that coumestrol, a coumestan-derivative, exhibited a selective inhibitory effect against MAO-A (IC50 = 1.99 ± 0.68 µM), a key target protein for depression. In a kinetics analysis with 0.5 µg MAO-A, 40–160 µM substrate, and 25 °C reaction conditions, coumestrol acts as a competitive MAO-A inhibitor with an inhibition constant of 1.32 µM. During an in silico molecular docking analysis, coumestrol formed hydrogen bonds with FAD and pi–pi bonds with hydrophobic residues at the active site of the enzyme. Moreover, based on thioflavin-T-based fluorometric assays, we elucidated that coumestrol effectively prevented self-aggregation of amyloid beta (Aβ), which induces an inflammatory response in the central nervous system (CNS) and is a major cause of Alzheimer’s disease (AD). Therefore, coumestrol could be used as a CNS drug to prevent diseases such as depression and AD by the inhibition of MAO-A and Aβ self-aggregation.

A neurogenic signature involving monoamine Oxidase-A controls human thermogenic adipose tissue development.

Mechanisms that control 'beige/brite' thermogenic adipose tissue development may be harnessed to improve human metabolic health. To define these mechanisms, we developed a species-hybrid model in which human mesenchymal progenitor cells were used to develop white or thermogenic/beige adipose tissue in mice. The hybrid adipose tissue developed distinctive features of human adipose tissue, such as larger adipocyte size, despite its neurovascular architecture being entirely of murine origin. Thermogenic adipose tissue recruited a denser, qualitatively distinct vascular network, differing in genes mapping to circadian rhythm pathways, and denser sympathetic innervation. The enhanced thermogenic neurovascular network was associated with human adipocyte expression of THBS4, TNC, NTRK3, and SPARCL1, which enhance neurogenesis, and decreased expression of MAOA and ACHE, which control neurotransmitter tone. Systemic inhibition of MAOA, which is present in human but absent in mouse adipocytes, induced browning of human but not mouse adipose tissue, revealing the physiological relevance of this pathway. Our results reveal species-specific cell type dependencies controlling the development of thermogenic adipose tissue and point to human adipocyte MAOA as a potential target for metabolic disease therapy.

Synthesis, biological evaluation and computational investigations of S-benzyl dithiocarbamates as the cholinesterase and monoamine oxidase inhibitors

The current study was aimed to identify the selective and multi-targeted inhibitors of cholinesterase and monoamine oxidase enzymes. For this purpose, a novel class of multi-targeted compounds i.e., S-benzyl dithiocarbamates (1-30) was synthesized via a single pot reaction and the structures were characterized via NMR (1H and 13C), FT-IR and high-resolution mass spectrometry (HRMS). Moreover, the purity of the final products was determined using thin-layer chromatography (TLC). The compounds were evaluated for their inhibitory potential against cholinesterases (ChE) and monoamine oxidases (MAO). Among all derivatives, compound 5 (2-(trifluoromethyl) benzyl azepane-1-carbodithioate) depicted the maximum inhibition of AChE and BChE enzyme with an IC50 value of 4.37±0.94 and 14.9±1.11, respectively. The derivative 11, expressed maximum inhibition of MAO-A and MAO-B with an IC50 value of 1.14±0.03 and 1.01±0.16 µM, respectively. Whereas, compound 16 exhibited maximum inhibitory potential against all four targeted enzymes i.e., AChE, BChE, MAO-A and MAO-B with an IC50 value of 1.39±0.07 µg/ mL, 1.52±0.14 µg/ mL, 44.9±1.54 µM and 2.85±0.21 µM, respectively. The chemical reactivity profile of the potent derivatives were evaluated through density functional theory studies (DFT) where it was found that compound 5, 6 and 11 possessed reactive character due to narrow LUMO/HOMO energy gap. In addition, Molecular docking studies revealed excellent docking scores and produced sable protein-ligand complexes. The stability of protein-ligand complex was affirmed by molecular dynamic simulations which revealed stable and equilibrated trajectories of simulated complexes. The findings of in-vitro and in-silico studies suggested compound 16 as a promising multi-targeted compound that can be act as lead molecule for the treatment of AD.

Nialamide in the treatment of depressive states

Depression is a mental disorder manifested by depressed mood, cognitive and motor retardation, and suicidal ideas. In the modern world, the number of cases of a combination of mental and somatic pathologies is increasing in medical practice. Therefore, the issue of studying and correctly prescribing antidepressants is crucial. It is necessary that the drug should not only treat the mental illness of the patient, but also should not harm his/her physical health. Nialamide belongs to antidepressants, the mechanism of which is non-selective and irreversible inhibition of MAO-A and MAO-B.

Design, Synthesis, and Monoamine Oxidase B Selective Inhibitory Activity of N-Arylated Heliamine Analogues.

Monoamine oxidase B (MAO-B) metabolizes monoamines such as dopamine regarding neural transmission and controls its level in the mammalian's brain. When MAO-B metabolizes dopamine abnormally, normal neurotransmission does not occur, and central nervous system disorders such as Parkinson's disease may develop. Although several MAO inhibitors have been developed, most of them have no selectivity between monoamine oxidase A (MAO-A) and MAO-B, or they work irreversibly against the enzyme. This report describes the first case of screening of N-arylated heliamine derivatives to develop novel MAO-B selective inhibitors that can be synthesized concisely by microwave-assisted Pd nanoparticle-catalyzed Buchwald-Hartwig amination. We discovered that the derivatives 4h, 4i, and 4j display inhibitory activity against MAO-B with IC50 values of 1.55, 13.5, and 5.08 μM, respectively.

The Synthesis of Schiff bases and new secondary amine derivatives of p-vanillin and evaluation of their neuroprotective, antidiabetic, antidepressant and antioxidant potentials

In the current study, five Schiff base derivatives coded as VDOPL (1), VHISL (2), V2-AFL (3), V4-AFL (4) and VAML (5) from p-vanillin were synthesized with dopamine, histamine, 2-aminophenol, 4-aminophenol and 4-aminomorpholine. Afterwards, these Schiff bases were reduced with NaBH4 to produce secondary amines coded as VDOPA (6), V2-AFA (7), V4-AFA (8) and VAMA (9). The chemical structures of the synthesized molecules were characterized by UV-Visible, FTIR, 1H-NMR, 13C-NMR, DEPT, APT, 1H, 1H-COSY, HMQC and HMBC methods. The enzyme inhibitory properties of p-vanillin, the primary amines, the Schiff bases and novel secondary amine derivatives on cholinesterase's (AChE and BChE) and on α-glycosidase and α-amylase enzyme activities were evaluated for the first time to determine their neuroprotective and antidiabetic effects, respectively. The antioxidant potentials of all molecules were also investigated by testing the ABTS and DPPH radical scavenging activities and reducing power. The neuroprotective, antidiabetic and antioxidant potentials of the molecules were also compared with the commercial drugs, neostigmine and galantamine (anticholinesterases), acarbose (antidiabetic), BHA and Trolox (antioxidants), respectively. The results of the molecules’ inhibitory effects on the AChE indicated that the neuroprotective effects of all molecules, except for VDOPL (1) are much weaker than the anticholinesterases, neostigmine and galantamine. VDOPL (1) demonstrated a potent inhibitory effect on the AChE with IC50=1.53 mg/mL. Whereas, it was proved that all of the tested molecules showed the stronger inhibitory effects against BChE enzyme than AChE enzyme, and VDOPL (1) and V2-AFL (3) were found to be the most effective inhibitors against both AChE and BChE enzymes among the tested molecules. The results on the antidiabetic potentials of the molecules showed that all synthesized molecules except V2-AFL (3) and VAML (5) inhibited α-glucosidase enzyme more potently than the antidiabetic agent, acarbose. Among the tested molecules, 4-aminophenol (IC50=0.44 mg/mL) and VDOPL (1) (IC50=0.45 mg/mL) were found to be the strongest inhibitors on α-glycosidase activity. However, all the tested molecules demonstrated the weaker inhibition effects as compared with the inhibition effect of the acarbose against α-amylase. Moreover, all of the tested molecules exhibited strong antioxidant potentials. Based on the current results, VDOPL (1) stands out as a target molecule for in vivo as well as clinical studies due to its potent neuroprotective, antidiabetic and antioxidant potentials. In addition, the antidepressant properties of p-vanillin, the Schiff bases and the secondary amines were tested for the first time against the MAO-A enzyme and their antidepressant properties were compared with the MAO inhibitor, clorgiline. The current results showed that p-vanillin (IC50=0.72 mg/mL), V2-AFL (3) (IC50=0.71 mg/mL), V2-AFA (7) (IC50=1.22 mg/mL) and V4-AFA (8) (IC50=2.36 mg/mL) are the potential antidepressant agents, despite the fact that the antidepressant effects were lower than that of clorgiline (IC50=0.34 mg/mL). However, the in vivo antidepressant properties, safeties and toxicities of the molecules should be investigated with further studies.

Natural Products Inhibitors of Monoamine Oxidases—Potential New Drug Leads for Neuroprotection, Neurological Disorders, and Neuroblastoma

Monoamine oxidase inhibitors (MAOIs) are an important class of drugs prescribed for treatment of depression and other neurological disorders. Evidence has suggested that patients with atypical depression preferentially respond to natural product MAOIs. This review presents a comprehensive survey of the natural products, predominantly from plant sources, as potential new MAOI drug leads. The psychoactive properties of several traditionally used plants and herbal formulations were attributed to their MAOI constituents. MAO inhibitory constituents may also be responsible for neuroprotective effects of natural products. Different classes of MAOIs were identified from the natural product sources with non-selective as well as selective inhibition of MAO-A and -B. Selective reversible natural product MAOIs may be safer alternatives to the conventional MAOI drugs. Characterization of MAO inhibitory constituents of natural products traditionally used as psychoactive preparations or for treatment of neurological disorders may help in understanding the mechanism of action, optimization of these preparations for desired bioactive properties, and improvement of the therapeutic potential. Potential therapeutic application of natural product MAOIs for treatment of neuroblastoma is also discussed.

Plant & Its Derivative Shows Therapeutic Activity on Neuroprotective Effect

In most cases, the death of neurons in certain parts of the brain is the defining feature of a condition that is classified as neurodegenerative. There have been studies conducted on both conventional and innovative drugs, however the results have shown that they only offer symptomatic advantages and come with a number of undesirable side effects. The finding of more potent compounds that can stop the pathophysiology of these diseases will be seen as a miracle in the present day. There is a wide variety of synthetic compounds accessible; nevertheless, these drugs may also create a broad range of additional health issues. As a consequence of this, scientists are looking to plants and other natural sources for the development of new medicines. In the practise of conventional medicine, it has been discovered that certain plants possess healing powers. The use of phytochemicals, which are produced from medicinal plants, may eventually replace the need for synthetic molecules. Numerous phytochemicals have been shown to be effective in the treatment of a wide range of diseases. This article discusses the potential therapeutic applications of plant-derived alkaloids for a number of neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), epilepsy, schizophrenia, and stroke. There are many different types of alkaloids that can be found in the plant kingdom. Some of these alkaloids include isoquinoline, indole, pyrroloindole, oxindole, piperidine, pyridine, aporphine, vinca, -carboline, methylxanthene, lycopodium, and erythrine byproducts. Alkaloids have a beneficial effect on the pathophysiology of these diseases because of their ability to act as muscarinic and adenosine receptor agonists, anti-oxidants, anti-amyloid and MAO inhibitors, acetylcholinestrase and butyrylcholinesterase inhibitors, an inhibitor of synuclein aggregation, dopaminergic and nicotine agonists, and NMDA antagonists.

Pharmacological Screening of Gentisic acid for Antidepressant Activity in Unstressed and Stressed Mice

Background: Gentisic acid has been reported to show neuroprotective effect. But its effect on depression is not available in the literature. So we evaluated the effect of this compound on depressive behavior in unstressed (normal) mice and stressed mice. Materials and Methods: Swiss albino male mice were given unpredictable mild stressors for twenty-one consecutive days to produce depressive behavior. Gentisic acid (25, 50, 100 mg/kg) and fluoxetine (20 mg/kg) were administered orally for twenty-one consecutive days. Depressive behavior was detected by tail suspension test and sucrose preference test. After behavioral testing, biochemical estimations were performed in plasma and brain. Histopathological studies on brain were also performed. Results: Immobility time of mice in tail suspension test was remarkably decreased by gentisic acid (50 and 100 mg/kg). Gentisic acid also restored decreased sucrose preference in mice subjected to stress paradigm. It remarkably lowered concentration of plasma nitrite, brain monoamine oxidase- A, malondialdehyde, TNF-α; and increased concentration of catalase and GSH in normal mice and also stressed mice. It also remarkably lowered plasma corticosterone concentration in stressed mice. Histopathological studies indicated protection by gentisic acid against hyperchromatic nuclei in brain. Conclusion: Gentisic acid produced remarkable antidepressant effect in normal mice and also stressed mice. The possible mechanisms for the observed antidepressant effect of gentisic acid might be through inhibition of brain MAO-A, amelioration of neuroinflammation and oxidative stress; and protection against hyperchromatic nuclei in brain. Moreover, antidepressant effect of gentisic acid in stressed mice might be through lowering of plasma corticosterone concentration.

Development of a Novel Class of Pyridazinone Derivatives as Selective MAO-B Inhibitors.

Sixteen compounds (TR1–TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 μM, followed by TR2 (IC50 = 0.27 μM). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in TR2 and TR16 increased the inhibitory activity of MAO-B. TR2 and TR16 were reversible MAO-B inhibitors that were competitive, with Ki values of 0.230 ± 0.004 and 0.149 ± 0.016 µM, respectively. The PAMPA method indicated that compounds TR2 and TR16 had the tendency to traverse the blood–brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases.

Synthesis, molecular modeling, 3D-QSAR and biological evaluation studies of new benzimidazole derivatives as potential MAO-A and MAO-B inhibitors

In this study, new 1-ethyl-2-substituted-5-(methylsulfonyl)-1H-benzimidazole derivatives were designed and synthesized as computer-aided potential MAO-A and -B inhibitors. Compounds E6 and E10 were found more active than reference compound moclobemide with IC50 (µM)= 0.096 ± 0.003 and 0.150 ± 0.006 against MAO-A, respectively. Compound E5, on the other hand, exhibited an activity close to the reference selegiline with IC50 (µM)= 0.045 ± 0.002 against MAO-B. The compounds were identified as potential inhibitors by molecular docking method and the protein-ligand interactions of compounds E5, E6, and E10 were described. The stability of the ligand of the MAO-B-E5 complex at the active site was revealed by molecular dynamics simulation. Comparative Molecular Field Analysis (CoMFA) models have been developed to identify the key structural fragments that allow inhibition on MAO-A and -B. The theoretical ADME calculations of the compounds were made, and it was found that they comply with the limiting rules. For detailed elucidation of compound structures, X-ray diffraction analysis of E4 compound was performed, as well as 1H-NMR, 13C-NMR, and HRMS analyzes.

Monoamine oxidase contributes to the metabolic memory in diabetic mice

Monoamine oxidase (MAO) with 2 isoforms, A and B, are mitochondrial enzymes that recently emerged as important cardiovascular sources of reactive oxygen species. The aim of the present study was to assess the contribution of monoamine oxidase (MAO) to the “metabolic memory” phenomenon, as mechanism underlying the persistent oxidative damage and endothelial dysfunction in an experimental model of diabetes mellitus in mice. We hypothesized that: (i) MAO is an important contributor to vascular oxidative stress, in context of diabetes, even after glucose normalisation and (ii) selective MAO-A and MAO-B inhibition (clorgyline and selegiline, 1 mg/kg/day, 1 week) will reduce oxidative stress and improve vascular reactivity. Our results showed that: (i) MAOs expression increased in mice aortas (assessed by qRT-PCR and immune fluorescence) after 2 weeks of hyperglycemia together with high ROS generation (assessed by spectophotometry and confocal microscopy – DHE staining) and impaired vascular relaxation, (ii) glucose normalization (glargine, 10 U/kg/day, 1 week) did not significantly reduced ROS generation, and (iii) in vivo administration of MAO inhibitors (in addition to insulin) reduced ROS levels and improved vascular relaxation in diabetic mice. In conclusion, MAOs represent a potential therapeutic target for vascular diabetic complications. MAO inhibitors are viable candidates for drug repurposing as vasculo-protective agents in diabetes. Research supported by the university internal grant code 6POSTDOC/1871/12.02.2020.