KR20190131792A - Composition for preventing or treating of neurological disorder comprising furanochalcone - Google Patents

Abstract

The present invention relates to a composition for preventing or treating neurological diseases comprising furanochalcone as an active component. Furanochalcone or a pharmaceutically acceptable salt thereof of the present invention exhibits an effect of selectively, reversibly, and competitively inhibiting the activity of monoamine oxidase B (MAO-B), associated with neurological diseases, and has little cytotoxicity, thereby being able to be safely used for a pharmaceutical composition or a food composition for preventing or treating neurological diseases. Therefore, furanochalcone is expected to be usefully used as a MAO-B reversible inhibitor that can inhibit the activity of novel MAO-B.

Description

Composition for preventing or treating neurological disorders comprising furanochalcone as an active ingredient

The present invention relates to a pharmaceutical composition or food composition for the prevention or treatment of neurological diseases, including furanochalcone or an acceptable salt thereof as an active ingredient.

In the past 50 years, Korea has undergone rapid industrial development, urbanization, westernization, nuclear familyization, higher education, aging, and informatization. This rapid development has resulted in high economic growth, but psychiatric disorders such as Parkinson's disease and dementia caused by aging, excessive gap between rich and poor, family breakup, alienation, and fierce competition. Neuropsychiatric disorders, such as depression and anxiety disorders, are on the rise.

Human monoamine oxidase (hMAOs) is a flavoenzyme family that degrades neurotransmitters and catalyzes the oxidation of monoamines such as serotonin and dopamine, and as a cofactor, flavin adenine dinucleotide (FAD) Include. hMAOs consist of two unique forms, hMAO-A and hMAO-B, encoded by separate genes, share about 70% of the amino acid sequence and have partially overlapping substrate specificities (JC Shih, et al. , Annu. Rev. Neurosci. 22 (1999) 197-217; and B. Mathew, et al., Curr. Enzyme Inhib. 11 (2015) 108-115). MAO-A isoenzyme is primarily involved in the metabolism of neurotransmitters such as adrenaline and serotonin, and MAO-B is involved in dopamine metabolism of dopaminergic neurons (C. Binda, et al., Curr. Top. Med. Chem. 11 (2011) 2788-2796). Recent studies have shown that MAO gene expression is important at early stages of embryonic development and brain formation (A. Whibley, et al., Eur. J. Hum. Genet. 8 (2010) 1095-1099). Treatment of neurological disorders such as depression and Parkinson's syndrome is a major goal of bioamines regulated by MAOs.

It is known that metabolism of monoamines in vivo plays an important role in the development of neuropsychiatric disorders, and the enzyme is known to be related to monoamine oxidase (MAO, E.C. 1.4.3.4).

Specifically, monoamine oxidase (MAO) is an enzyme that is widely distributed in the central nervous system and peripheral tissues, and is derived from monoamine-based compounds and enteric bacteria which are neurotransmitters by catalyzing the oxidative deamine reaction of amine compounds. Break down hormonal amines. In other words, the neurotransmitter is decomposed by the monoamine oxidase, resulting in a deficiency of the monoamine-based compound in vivo and the development of neuropsychiatric disorder.

The monoamine oxidase (MAO) mainly uses dopamine, tyramine, epinephrine, or norepinephrine as an endogenous substrate, and selectively deselects serotonin depending on substrate specificity. It can be divided into two types, A-type (type A, MAO-A) for amination, and B-type (type B, MAO-B) for selectively deamination of phenylethylamine and benzylamine. (Youdim MB et al. , 2006, Nat. Rev. Neurosci., 7: 295-309). Among these, MAO-A is associated with the development of neuropsychiatric diseases such as depression and anxiety, and MAO-B is associated with the development of neurological diseases such as Alzheimer's diseases and Parkinson's diseases.

Thus, MAO inhibitors have been used at home and abroad to prevent or treat neuropsychiatric disorders, which MAO-A selective inhibitors, MAO-B selective inhibitors, and MAO-A / B non-selective inhibitors, further reversible and irreversible Are classified as inhibitors [Malcomson T et al. , 2015, FEBS J., 282: 3190-3198; Mostert S et al. , 2015, Chem. Med. Chem., 10: 862-873.

Inhibitors of MAO-B can preserve dopaminergic neoplasmic neurons by preventing the underlying neurodegenerative processes that can recommend inpatients treated with levodopa in Parkinson's disease as adjuvant therapy. Currently used clinically, MAO-B inhibitors are inherently irreversible but selectively show long-lasting inhibition resulting in new enzyme biosynthesis in the human brain. In addition, irreversible MAO inhibitors showed potential immunogenicity, weak pharmacokinetic properties, increased duration of action and weak pharmacokinetic properties of enzyme inhibitor adducts. On the other hand, administration of a reversible MAO-B inhibitor restores enzyme activity when the inhibitor is not present in the tissue. Therefore, the design and synthesis of reversible types of selective MAO-B inhibitors have attracted much more attention in the treatment of Parkinson's disease. Numerous compounds and drugs have been recently discovered that selectively target these variants. These agents are synthetic compounds or natural products and derivatives such as chalcone, pyrazole, chromone, coumarin, xanthine, isatin derivatives, thiazolidinedione (thiazol-2-yl) hydrazones and commercially available drugs.

Therefore, the present inventors searched for a compound that is safe for long-term use and has a stronger MAO-B inhibitory activity, and inhibits the inhibitory activity of MAO-A and MAO-B against 12 compounds which are furan substituents of chalcone known as inhibitors of hMAO-B. It was confirmed that this furanochalcon has a strong inhibitory activity against MAO-B, and completed the present invention.

Therefore, the technical problem to be solved in the present invention is to provide a composition for the prevention or treatment of neurological diseases.

In order to solve the above technical problem, the present invention provides a pharmaceutical composition for the prevention or treatment of neurological diseases, including furanochalcon or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a food composition for the prevention or improvement of neurological diseases, including furanochalcone or a food acceptable salt thereof as an active ingredient.

The composition comprising the furanochalcone or an acceptable salt thereof according to the present invention as an active ingredient can be used to treat or prevent any subject with or at risk for neurological diseases such as Alzheimer's disease and Parkinson's disease.

Representative neurological diseases that can be treated according to the present invention include vascular dementia, senile dementia in the form of Alzheimer's disease, minimal cognitive impairment, Lewy body dementia, Huntington's disease dementia, Pick's disease, prion disease-related dementia, HIV-related dementia, prefrontal lobe Dementia, hippocampus-related dementia and demyelinating diseases (e.g., multiple sclerosis (MS), progressive multifocal white encephalopathy (PML), disseminated necrotic white encephalopathy (DNL), acute disseminated encephalomyelitis, Silder's disease, Central phacolytic lysis (CPM), radiation necrosis, Vince-Banger's disease (SAE), Blaine Barre syndrome, cerebral white matter dystrophy, acute disseminated encephalomyelitis (ADEM), acute transverse myelitis, acute viral encephalitis, adrenal protein dystrophy ( ALD), spinal neuropathy, AIDS-phobia myelopathy, autoimmune encephalomyelitis (EAE), autoimmune neuritis (EAN), HTLV-associated myelopathy, Lever's inherited visual nerve atrophy, subacute sclerotic proencephalitis and tropical stiffness Cerebral degenerative diseases, including renal paralysis, Parkinson's disease, Alzheimer's disease, prion-related diseases, mental illnesses (e.g. dimness, depression, anger, attention deficit disorders, autism, behavioral / performance disorders, dissociative disorders, Eating disorders, alcoholic fetal syndrome, inability to learn, intellectual disabilities, mood disorders, speech disorders, substance abuse, suicide, Tourette disorders and post-traumatic stress syndrome, seizure and cramping disorders (e.g. epilepsy), analgesia (e.g. Central and peripheral), including acute, chronic and mental), migraine and acute cerebral degenerative diseases such as trauma and seizures. Any of these diseases can be treated using the methods and compositions described herein.

As used herein, the term "prevention" refers to inhibiting the occurrence of a disease or condition in an individual who has not been diagnosed as having a disease or condition but is prone to such disease or condition.

As used herein, the term “treatment” means (a) suppression of the development of a disease or disorder in a subject (b) alleviation of a disease or disorder and (c) removal of the disease or disorder.

As used herein, the term "individual" refers to monkeys, cows, horses, pigs, sheep, dogs, cats, rats, mice, chimpanzees, and the like, including humans with diseases that may improve symptoms by administering the composition of the present invention. Means mammal.

Furanochalcone, an active ingredient of the composition of the present invention, is a furan substituted chalcone analogue, preferably (2E, 4E) -1- (furan-2-yl) -5-phenyl penta-2,4-diene-1 -On.

The furanochalcone of the present invention can be used in the form of a pharmaceutically acceptable salt or a food acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, Xylene Sulfonate, Phenyl Acetate, Phenylpropionate, Phenyl Butyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate , Naphthalene-2-sulfonate or mandelate.

The acid addition salts according to the invention are dissolved in conventional methods, for example, furanochalcone in an excess of aqueous acid solution, and the salts are prepared using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation. In this mixture, the solvent or excess acid may be evaporated to dryness, or the precipitated salt may be prepared by suction filtration.

Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).

Furanochalcone of the present invention has the effect of selectively, reversibly and competitively inhibiting the activity of monoamine oxidase type B (MAO-B), which is associated with the development of neurological diseases.

Therefore, the composition comprising furanochalcone of the present invention as an active ingredient can be usefully used for the purpose of preventing or treating neurological diseases.

Furanochalcone included as an active ingredient in the composition of the present invention is included in an amount of 0.001 to 50% by weight, preferably 0.01 to 30% by weight, more preferably 0.01 to 10% by weight based on the total weight of the total composition. Can be. When the content of the furanochalcone is less than 0.001% by weight of MAO-A inhibitory activity is weak, when the content of more than 50% by weight may be inefficient because the effect increase is not proportional to increase the content, ensuring the stability of the formulation There is no problem.

As one specific use of the present invention, the composition of the present invention can be used as a pharmaceutical composition for preventing or treating neurological diseases.

When the composition of the present invention is used as a pharmaceutical composition, it may further include a pharmaceutically acceptable carrier in addition to furanochalcone as an active ingredient. Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are commonly used in the preparation of carbohydrate compounds (eg, lactose, amylose, dextrose, sucrose, sorbitol, mannitol, starch, cellulose, etc.). , Acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, salt solution, alcohol, gum arabic, vegetable oil (e.g. corn oil, cotton seed oil) , Soymilk, olive oil, coconut oil), polyethylene glycol, methyl cellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil, and the like. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories, and sterile injectable solutions according to conventional methods.

The pharmaceutical composition may prevent or treat neurological diseases. The method of treatment may include administering the pharmaceutical composition in a pharmaceutically effective amount in various routes in mammals such as rats, mice, livestock, humans, and the like. The method of administration may be in any manner, for example, oral, rectal or intravenous infusion, intraperitoneal administration, intramuscular administration, or cerebrovascular administration.

The dosage of the pharmaceutical composition may vary depending on factors such as the formulation method, mode of administration, age, weight, sex, and morbidity of the patient, and may be appropriately selected by those skilled in the art. In general, the pharmaceutical composition of the present invention may be administered in an amount of 0.001-100 mg / kg divided into once or several times daily. However, the above dosage does not limit the scope of the present invention in any aspect.

As another specific use of the present invention, the composition of the present invention can be used as a food composition for preventing or ameliorating neurological diseases.

As used herein, the term "improvement" refers to any action that improves the condition of a disease or condition in an individual.

When the composition of the present invention is used as a food composition, in addition to the furanochalcone as an active ingredient, ingredients that are commonly added during food production, such as proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents, etc. It may include.

Examples of such carbohydrates are monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like and xylitol, sorbitol, erythritol. As flavoring agents, natural flavoring agents (tauumatin, stevia extract (for example rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.

In addition to the above-mentioned ingredients, the food composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, Alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the food composition of the present invention may contain fruit flesh for the production of natural fruit juices, beverages and vegetable beverages. These components can be used independently or in combination.

There is no particular limitation on the kind of food. Examples of the food to which the furanochalcone of the present invention can be added include meat, sausage, bread, chocolate, candy, snacks, confectionary, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, Teas, drinks, alcoholic beverages and vitamin complexes and the like, and includes all of the health food in the conventional sense.

When the food composition of the present invention is prepared with a drink, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, and the like may be further included in addition to the furanochalcone of the present invention.

In addition, the food composition of the present invention may further include a food additive, and the suitability as a food additive, unless otherwise specified in accordance with the General Regulations of the Food Additives Code and General Test Methods, etc. approved by the Food and Drug Administration (KFDA) Judge according to the standards and standards for the item.

Examples of the items loaded on the food additives are chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid and cinnamon acid; Natural additives such as crystalline cellulose and guar gum; Sodium L-glutamate preparations; Noodle addition alkaline agent; Preservative preparations; Mixed preparations, such as a tar coloring agent, etc. are mentioned.

On the other hand, furanochalcone of the present invention is a harmless substance without cytotoxicity. Therefore, the furanochalcone of the present invention can be used safely even in long-term use, in particular can be used safely in the pharmaceutical or food composition as described above.

Furanochalcone or an acceptable salt thereof of the present invention exhibits the effect of selective, reversible, and competitively inhibiting the activity of monoamine oxidase type B (MAO-B), which is associated with neurological diseases, and has little cytotoxicity. It can be used safely in pharmaceutical or food compositions for preventing or treating neurological diseases. Thus, furanochalcone or acceptable salts thereof are expected to be useful as MAO-B reversible inhibitors that can inhibit the activity of novel MAO-B.

1 shows an Oak Ridge Thermal Ellipsoid Plot (ORTEP) diagram of a furanochalcone molecule.
2 shows recovery of MAO activity after dilution of MAO-A (A) and MAO-B (B) enzymes inhibited by furanochalcone.
3 is a lineweaver-burg plot of inhibition of MAO-A (A) and MAO-B (C) by furanochalcon and gradients for inhibitor concentrations of MAO-A (B) and MAO-B (D). The second plot is shown.
4 shows the docking pose of F1 at the MAO-B active site.

Hereinafter, the present invention will be described in more detail with reference to examples. These examples and the like are only for illustrating the present invention in more detail, it is to those skilled in the art that the scope of the present invention is not limited by these reference examples and examples, etc. according to the gist of the present invention. Will be self-evident.

Material preparation

Benzylamine, kinuramine, toloxatone, razabemide and recombinant human MAO-A and MAO-B were purchased from Sigma-Aldrich (St. Louis, MO); Benzylamine, kinuramine, toloxatone, razabemide and recombinant human MAO-A and MAO-B were purchased from Sigma-Aldrich (St. Louis, MO); Chlorgiline and pargiline were obtained from the monoamine oxidase kit (BioAssay Systems (Hayward, Ca. USA)) and used as reference inhibitors of MAO-A and MAO-B. MAO-A and MAO-B were stored at −70 ° C. in 100 mM potassium phosphate (pH 7.4) containing 0.25 M sucrose, 0.1 mM EDTA and 5% glycerol.

Reference Example 1 Initial Oxidation Rate Measurement of MAO

The initial oxidation rate of MAO was measured at 25 ° C. in 1 ml cuvette containing 50 mM sodium phosphate (pH 7.4). The activity of MAO-A was analyzed for 20 minutes at 316 nm using 0.06 mM kynuramine (1.7 XK _m ) as substrate, and the activity of MAO-B was measured at 250 nm using 0.6 mM benzylamine (3.8 XK _m ). Analysis for 30 minutes. The reaction rate was expressed as a change in absorbance per minute. The K _m value for kynuramine was 0.036 mM and the K _m value for benzylamine was 0.16 mM.

Example 1 Synthesis of Furanochalcone Compound

Equimolar amounts of 2-acetyl furan and aromatic or heteroaromatic aldehydes were stirred in ethanol (30 mL). Sodium hydroxide (50%) (10 mL) was added. When the reaction was complete the reaction mixture was poured onto crushed ice. The solid product obtained was filtered, washed, dried and recrystallized from ethanol.

Heterocyclic chalcone analogs F1 to F12 were synthesized in alkaline sodium hydroxide in a yield of 60-90% by Claisen-Schmidt condensation between furan 2-aldehyde and cycloaromatic methyl ketone as shown in Scheme 1 below. The structure and IR of furanochalcone were confirmed by ¹ H NMR, ¹³ C NMR and mass spectrometry. The structure of F1 (furanochalcone) was determined using single X ray diffraction analysis. 1 shows an Oak Ridge Thermal Ellipsoid Plot (ORTEP) diagram of a furanochalcone molecule.

Scheme 1

Example 2 Measurement of MAO-A and MAO-B Inhibitory Activity against Furanochalcone

Inhibitory activity of MAO-A and MAO-B of 12 furanochalcon analogs (F1 to F12) was analyzed; IC ₅₀ values are shown in Table 1 below.

As a result of preliminary testing of inhibitory activity against inhibitors of 10-40 μM, the K _i values of effective compounds showing 25% or more inhibitory activity at 40 μM were determined by kinetic studies. Kinetics of MAO-A and MAO-B inhibition by the compounds were investigated using kynuramine and benzylamine as substrates at substrate and inhibitor concentrations, respectively. Catalyst rates of MAO-A and MAO-B were measured at five different substrate concentrations (0.006 to 0.15 mM and 0.06 to 1.5 mM, respectively) in the absence or presence of inhibitors.

MAO-A selectivity index was arithmetic using IC ₅₀ (MAO-B) / IC ₅₀ (MAO-A).

Inhibition experiments in the presence of 10 μM or 40 μM compounds showed a wide range of titers. Ki values were determined for compounds exhibiting at least 25% inhibitory activity. As shown in Table 1, it was found that most of the test compounds showed superior inhibitory activity against hMAO-B than hMAO-A. Compound (2E, 4E) -1- (furan-2-yl) -5-phenyl penta-2,4-dien-1-one (F1) in the analog is potent and selective with an inhibition constant (K _i ) of 0.0041 μM. MAO-B inhibitory activity, and selectivity index (SI) was 172.4. Inhibition activity was significantly increased by the introduction of cinnamic wheat into furalocacon. Compound (F8) incorporating a benzothiophene ring into furanochalcon also exhibited selective MAO-B inhibitory activity with an inhibition constant (Ki) value of 0.072 μM and an SI of 12.6. Electron donation of a methoxy group and a hydroxyl group to the B ring of furanochalcone reduced the inhibitory activity against hMAO. In addition, the introduction of a bromine atom at the ortho position of the phenyl system showed 11.8% and 15% of inhibitory action against MAO-A and MAO-B at 40 µM.

In this experiment, it was found that various structural modifications such as changes in the substituents of furanochalcone, introduction of substituents, and enlargement of the B ring have a significant effect on MAO-A and MAO-B inhibition. Previously, Desideri et al. Demonstrated that the expansion of chalcone linkers by carbon-hydrocarbon-carbon olefin units showed potent MAO-B inhibitory activity (N. Desideri, et al., Eur. J. Med. Chem. 59 (2013) 91-100). The same trend was observed for the F1 molecule, with two olefin units present between the furan and phenyl systems of the scaffold associated with high π-electron density, which is responsible for the interaction of the co-factor of MAO-B with the flavin nucleus. Can contribute.

Example 3 Reversibility Measurement of Furanocalcon on MAO-B Inhibition

To investigate the reversibility of the effective inhibitors, recovery of MAO activity after dilution of the inhibited enzyme was analyzed as follows. IC ₅₀ values of F1 or F8 were determined by building S-shaped curves of residual MAO activity versus various inhibitor concentrations. MAO-A or MAO-B was diluted with excess F1 or F8 (100 ㅧ IC ₅₀ ) for 15 min and the mixture was diluted 100 fold (ie 1.0 ㅧ IC ₅₀ ). Residual activity was measured and compared to activity under undiluted conditions (ie 1.0 kPa IC ₅₀ from the start of the experiment). Chlorogiline and paragiline were used as reference irreversible inhibitors for MAO-A and MAO-B using a preincubation time of 15 minutes each.

2 shows recovery of MAO activity after dilution of MAO-A (A) and MAO-B (B) enzymes inhibited by furanochalcone. In (A) Toloxatone was used as a reference irreversible MAO-A inhibitor. In (B), pargyline was used as a reference irreversible MAO-B inhibitor.

As shown here, the IC ₅₀ values of F1 for MAO-A and MAO-B were 1.75 ± 0.14 and 0.0395 ± 0.0064 μM, respectively. F8 was 1.90 ± 0.035 and 0.59 ± 0.064 μM, respectively. In the dilution recovery experiments, the residual activity of the MAO-A and MAO-B by F1 at dilution conditions was 103.5% (57.1% to 59.1%) and 112.7% (56.0% to 63.1%), respectively, compared to the undiluted state Recovered. The activity of MAO-A and MAO-B by F8 was fully recovered to 104.1% (53.3% to 55.5%) and 112.5% (55.1% to 62.0%), respectively. However, chlorgiline showed less than half of the activity level, ie 47.2%, and pargiline showed insignificant activity, ie 3.9%. These results indicate that F1 and F8 are reversible inhibitors.

Example 3 Measurement of MAO-A Inhibitory Activity According to the Puranocalcon Concentration or Substrate Concentration

MAO-A and MAO-B inhibition modes by furanochalcone were tested using different concentrations of substrate and inhibitor. Its inhibition modalities and K _i values were determined using a Lineweaver-Burk plot.

3 is a lineweaver-burg plot of inhibition of MAO-A (A) and MAO-B (C) by furanochalcon and gradients for inhibitor concentrations of MAO-A (B) and MAO-B (D). The second plot is shown. Inhibitor concentrations of F1 ranged from 0 to 0.5 μM for MAO-A and 0 to 0.1 μM for MAO-B. Kinuramin and benzylamine were used at five concentrations (0.006 to 0.15 mM and 0.06 to 1.5 mM, respectively). Initial velocity was expressed as increased absorbance per minute.

As shown in FIG. 3, the plot for MAO-A and MAO-B inhibition by F1 was linear and crossed the y axis (A and C). This means that F1 is a competitive inhibitor of MAO-A and MAO-B. The K _i values for inhibition of MAO-A and MAO-B by F1 in the second plot of slope for inhibitor concentration were 0.707 ± 0.034 and 0.0041 ± 0.0008ΔM, respectively (B and D). These results indicate that F1 is a competitive inhibitor of MAO-A or MAO-B and inhibits MAO-B more effectively.

Example 4 Molecular MAO Docking Simulation of Furanochalcone

The MAO-B inhibitory activity was simulated for MAO docking with the focus on the largest and selective compound F1. In the present molecular simulation study, AUTODOCK4.2 software was used to establish a ligand-based computer modeling program for predicting the binding energy of selected compounds with hMAO isoforms. The docking protocol was performed using the X-ray crystal structures of hMAO-A (2BXR) and hMAOB (2BYB) downloaded from the Protein Data Bank (www.rcsb.org). Protein preparation was performed using Maestro-8.5 Protein Preparation Wizard (Schrodinger LLC). Ligands were prepared via PRODRG web server (http://davapc1.bioch.dundee.ac.uk/cgi-bin/prodrg). Grid preparation and docking parameters were created based on the reported method (B. Mathew, et al., Biomed. Aging Pathol. 4 (2014) 327-333).

4 shows the docking pose of F1 at the MAO-B active site. The yellow mesh here represents the π-π stacking interaction. The highest scoring molecules of the largest clusters were analyzed by interaction with the protein. MAO-B inhibitors have a high binding affinity of polar and nonpolar interactions with substrate and inlet cavities to the inhibitor binding cavities (IBC) of enzymes (OM Abdelhafez, et al., J. Med. Chem. 55 (2012) 10424-10436). However, such treatments are not possible with the leading compounds of the present invention which mainly have furan and phenyl-based hydrophobic moieties separated by unsaturated ketone systems. In the visual inspection, the furan nucleus is located against the FAD official on the side of the inlet gorge surrounded by phenolics. Strong π-π stacking interactions appeared between the phenyl system and the FAD nucleus.

As described above, in the present invention, a series of 12 furan derivatives were synthesized and evaluated in vitro for MAO-A and MAO-B inhibitory activity. Most compounds have been found to be potent and selective inhibitors of MAO-B rather than MAO-A, and in particular the compounds of F1 and F8 in analogs of F1 to F12 are reversible inhibitors of MAO-B. The Ki value of F1 (0.0041 μM) was the lowest value of the chalcone derivatives reported so far, and also lower than that of the commercially available drug reversible MAO-B inhibitor lazabemide (0.0079 μM). Therefore, based on these results, furanochalcone is expected to be useful as a MAO-B reversible inhibitor that can strongly inhibit the activity of MAO-B.

Claims (6)

Pharmaceutical composition for the prevention or treatment of neurological diseases, including furanochalcone (furanochalcone) or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 1,
The furanochalcone is (2E, 4E) -1- (furan-2-yl) -5-phenyl penta-2,4-dien-1-one pharmaceutical composition for the prevention or treatment of neurological diseases. The method of claim 1,
The neurological disorders include vascular dementia, senile dementia, minimal cognitive impairment, Lewy body dementia, Huntington's disease dementia, Pick's disease, prion disease-related dementia, HIV-related dementia, prefrontal dementia, hippocampal dementia-related dementia, demyelinating disease, Parkinson's disease, Alzheimer's disease, prion-related diseases, mental disorders, seizures, cramps disorders and analgesic, pharmaceutical composition for the prevention or treatment of neurological diseases, characterized in that pain. Food composition for the prevention or improvement of neurological diseases, including furanochalcone or a food acceptable salt thereof as an active ingredient. The method of claim 4, wherein
The furanochalcone is (2E, 4E) -1- (furan-2-yl) -5-phenyl penta-2,4-dien-1-one food composition for the prevention or improvement of neurological diseases. The method of claim 4, wherein
The neurological disorders include vascular dementia, senile dementia, minimal cognitive impairment, Lewy body dementia, Huntington's disease dementia, Pick's disease, prion disease-related dementia, HIV-related dementia, prefrontal dementia, hippocampal dementia-related dementia, demyelinating disease, Parkinson's disease, Alzheimer's disease, prion-related diseases, mental disorders, seizures, cramps disorders and analgesic food composition for the prevention or improvement of neurological diseases, characterized in that pain.

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