Synthetic and Natural Monoamine Oxidase Inhibitors as Potential Lead Compounds for Effective Therapeutics (original) (raw)
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Selective MAO-B inhibitors: a lesson from natural products
Molecular Diversity, 2013
Monoamine oxidases (MAOs) are mitochondrial bound enzymes, which catalyze the oxidative deamination of monoamine neurotransmitters. Inside the brain, MAOs are present in two isoforms: MAO-A and MAO-B. The activity of MAO-B is generally higher in patients affected by neurodegenerative diseases like Alzheimer's and Parkinson's. Therefore, the search for potent and selective MAO-B inhibitors is still a challenge for medicinal chemists. Nature has always been a source of inspiration for the discovery of new lead compounds. Moreover, natural medicine is a major component in all traditional medicine systems. In this review, we present the latest discoveries in the search for selective MAO-B inhibitors from natural sources. For clarity, compounds have been classified on the basis of structural analogy or source: flavonoids, xanthones, tannins, proanthocyanidins, iridoid glucosides, curcumin, alkaloids, cannabinoids, and natural sources extracts. MAO inhibition values reported in the text are not always consistent due to the high variability of MAO sources (bovine, pig, rat brain or liver, and human) and to the heterogeneity of the experimental protocols used.
NOVEL MAO INHIBITORS FOR PARKINSON’S
Parkinson disease (PD) is the second most common neurodegenerative disorder. MAO A and MAO B have important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system. Monoamine oxidase inhibitors may limit the rate of dyskinesia relative to levodopa, the standard therapy for motor control of PD. The MAOs site represents a central target for therapeutics of Parkinson's disease and major depressive disorder. Monoamine Oxidase (MAOs) isoforms have amine oxidase domain (IPR001613, IPR002937), we have taken the functional signature part to study their homologues in human genome and successfully hunted 14 isoforms related to this family. Templates were selected with 99% sequence identity for both Mao A and Mao B isoforms. 3D structure of MAO A and MAO B were generated, evaluated and submitted to PMDB database and are available with PMDBID; PM0077964, PM0077935 respectively. Some novel herbal bioactive compounds (Baicalin, Curcumin and Dronabinol) have been reported to be useful in neurodegerative disorders, depression and have antioxidative property. Docking was successfully performed for MAO A and MAO B proteins with Baicalin, Curcumin and Dronabinol bioactive compounds and active site coordination was found to be similar as the template residues involved in binding with experimentally used inhibitors. The residues which are involved in the hydrophobic, cation-pi, pi-pi interaction and hydrogen bonding etc. also representing the similarity with the predicted active sites-1 by using Q-site finder with major interacting surface area. Among these three compounds, most effective compound was found to be Dronabinol as showing minimum Inhibition Constant, Ki and lowest free energy of binding for both models. This knowledge may be important for the development of novel drugs for the treatment of Parkinson disease and other neurodegenrative disorders.
Herbal Natural Products As a Source of Monoamine Oxidase Inhibitors: A Review
Current Topics in Medicinal Chemistry, 2012
Drugs of natural origin still play a major role in the treatment of many diseases and as lead structures for the development of new synthetic drug substances. This review article deals the pharmacological effects on the Central Nervous System (CNS) of some plant extracts and their isolated chemical components due to their monoamine oxidase (MAO) activity. Herbs and herbal preparations containing MAO-A inhibitors have been widely used as an effective alternative in the treatment of neuropsychiatric diseases such as depression. Inhibitors of MAO-B not only enhance dopaminergic neurotransmission but also prevent activation of toxin and free radical formation, alleviating the process of neuron denaturalization, on account of which they are used in Parkinson disease (PD). Several methods have been developed for monitoring MAO activity and its inhibitor screening of bioactive natural products.
High throughput Screening to Identify Natural Human Monoamine Oxidase B Inhibitors
Phytotherapy Research, 2012
Age-related increase in monoamine oxidase B (MAO-B) may contribute to CNS neurodegenerative diseases. Moreover, MAO-B inhibitors are used in the treatment of idiopathic Parkinson disease as preliminary monotherapy or adjunct therapy with L-dopa. To date, meager natural sources of MAO-B inhibitors have been identified, and the relative strength, potency and rank of many plants relative to standard drugs such as Selegiline (L-deprenyl, Eldepryl) are not known. In this work, we developed and utilized a high throughput enzyme microarray format to screen and evaluate 905 natural product extracts (0.025-.7 mg/ml) to inhibit human MAO-B derived from BTI-TN-5B1-4 cells infected with recombinant baculovirus. The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis-matrix assisted laser desorption ionization-time-of-flight-tandem mass spectroscopy, and enzyme activity was confirmed by [1] substrate conversion (3-mM benzylamine) to H 2 0 2 and [2] benzaldehyde. Of the 905 natural extracts tested, the lowest IC 50 s [<0.07 mg/ml] were obtained with extracts of Amur Corktree (Phellodendron amurense), Bakuchi Seed(Cyamopsis psoralioides), Licorice Root (Glycyrrhiza glabra/uralensis), Babchi (Psoralea corylifolia seed). The data also show, albeit to a lesser extent, inhibitory properties of herbs originating from the mint family (Lamiaceae) and Turmeric, Comfrey, Bringraj, Skullcap, Kava-kava, Wild Indigo, Gentian and Green Tea. In conclusion, the data reflect relative potency information by rank of commonly used herbs and plants that contain human MAO-B inhibitory properties in their natural form.
A QSAR study of some Phenoxyacetamide derivatives as a MAO-A inhibitor
International Journal of Research and Development in Pharmacy & Life Sciences, 2018
Antidepressants are the most prescribed therapy for depression. The prevailing theory is that antidepressants increase the concentration of one or more brain chemicals (neurotransmitters) that nerves in the brain use to communicate with one another. The neurotransmitters affected by antidepressants are norepinephrine, serotonin, and dopamine. In order to address the need for new MAO inhibitors with less side effects, we can aim compounds previously discovered for their potential as MAOIs. Among them, safinamide was reported to be a potent anti-MAO B agent, and milacemide, which was found to be a potent MAO inhibitor and a prodrug for glycine. The present work deals with the aim because Currentely available MAO inhibitors {Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Emsam), Tranylcypromine (Parnate) etc} develop side effects because they do not selectively for MAO-A and MAO-B. So, the present study is focused to develop potent selective MAO-A inhibitors, to treat depression, that may be of better pharmacological activity with less adverse effect.
Current neuropharmacology, 2018
The computational development of human monoamine oxidase (MAO) inhibitors led to advancement in drug design and the treatment of many neurodegenerative diseases and neuropsychiatric disorders. The computational development of human monoamine oxidase (MAO) inhibitors led to advancement in drug design and the treatment of many neurodegenerative diseases and neuropsychiatric disorders. Different natural heterocyclic structures are reported to display selective MAO inhibitory activity by preclinical and in-silico modeling. Currently, the major interest is devoted to the study of natural based therapeutic agents from the different categories. Therefore, we presenting the review to critically discuss and outline the recent advances in our knowledge on the importance of natural and natural based ligand-MAO insilico methods for novel MAO inhibitors. Several natural and related synthetic heterocyclic compounds such as coumarins, β- carboline, piperine, naphthoquinone, morpholine, caffeine, a...
Journal of Enzyme Inhibition and Medicinal Chemistry, 2012
Monoamine oxidase (MAO) enzymes catalyze the oxidative deamination of amines and neurotransmitters and inhibitors of MAO are useful as neuroprotectants. This work evaluates the human MAO-catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopaminergic neurotoxin, to the directly-acting neurotoxic metabolites, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP +) and 1-methyl-4-phenylpyridinium (MPP +) measured by High-Performance Liquid Chromatography (HPLC), and this approach is subsequently used as a new method for screening of MAO inhibitors and protective agents. Oxidation of MPTP by human MAO-B was more efficient than by MAO-A. R-Deprenyl, a known neuroprotectant, norharman (β-carboline), 5-nitroindazole and menadione (vitamin K3) inhibited MAO-B and reduced the formation of toxic pyridinium cations. Clorgyline and the β-carbolines, harman and norharman, inhibited the oxidation of MPTP by MAO-A. Cigarette smoke, as well as the naturally occurring β-carbolines (norharman and harman) isolated from smoke and coffee inhibited the oxidation of MPTP by MAO-B and/or MAO-A, suggesting protective effects against MPTP. The results show the suitability of the approach used to search for new MAO inhibitors with eventual neuroprotective activity.
Flavonoid Derivatives for Monoamine Oxidase–A Inhibition
Advanced Journal of Chemistry, Section B, 2019
The in silico molecular docking (MD) simulations have been performed to examine the efficacy of three flavonoid ligands including chrysin, apigenin and luteolin on monoamine oxidase-A (MAO-A) enzyme inhibitions in comparison with the reference moclobemide inhibitor. All the obtained quantitative and qualitative results indicated that the flavonoid ligands could be proposed as possible inhibitors for MAO-A enzyme activity. The most important note is that the ligands could interact with the coenzyme of MAO-A, which is dominant for enzyme inhibition. The results indicated that luteolin could be proposed as the best choice of MAO-A enzyme inhibitor among the investigated ligands.
Relevance of benzyloxy group in 2-indolyl methylamines in the selective MAO-B inhibition
British Journal of Pharmacology, 1999
Previous studies with indolyl derivatives as monoamine oxidase (MAO) inhibitors have shown the relevance of the indole structure for recognition by the active site of this enzyme. We now report a new series of molecules with structural features which determine the selectivity of MAO inhibition. 2 A benzyloxy group attached at position 5 of the indole ring is critical for this selective behaviour. Amongst all of these benzyloxy-indolyl methylamines, N-(2-propynyl)-2-(5-benzyloxyindol)methylamine FA-73 was the most potent MAO-B`suicide' inhibitor studied. 3 The K i values for MAO-A and MAO-B were 800+60 and 0.75+0.15 nM, respectively. These data represent a selectivity value of 1066 for MAO-B, being 48 times more selective than L-deprenyl (K i values of 376+0.032 and 16.8+0.1 nM for MAO A and MAO-B, respectively). The IC 50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150+8 mM for FA-73 and 68+10 mM for L-deprenyl whereas in human caudate tissue the IC 50 values were 0.36+0.015 mM for FA-73 and 0.10+0.007 mM for L-deprenyl. Moreover, mouse brain MAO-B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg 71 adminstration, MAO-A activity was not aected. 4 These novel molecules should provide a better understanding of the active site of monoamine oxidase and could be the starting point for the design of further selective, non-amphetamine-like MAO-B inhibitors with therapeutic potential for the treatment of neurological disorders.
α-Ketoamino acid ester derivatives as promising MAO inhibitors
Bioorganic & Medicinal Chemistry Letters, 2015
OxymaPure p-Aminobenzoic acid Monoamine oxidase inhibitors a b s t r a c t a-Ketoamino acid ester 2-[2-(2-acetamidophenyl)-2-oxoacetamido] and 2-[4-(2-(2-acetamidophenyl)-2oxoacetamido)benzamido] derivatives were synthesized via the ring opening of N-acetylisatin under mild conditions. These compounds were then examined for their capacity to inhibit monoamine oxidase (MAO). The inhibition profile was found to be competitive for compounds 4d, 6a, 6b and 6f, which showed MAO-A selectivity. Observation of the docked positions of these compounds revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Our findings indicate that the members of this family of a-ketoamino acid esters are promising MAO inhibitors.