Potent Monoamine Oxidase Inhibitors Research Articles

Discovery of monoamine oxidase inhibitors by medicinal chemistry approaches.

Neuropsychiatric disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and depression, have seriously inconvenienced the lives of patients. Growing evidence indicates that these diseases are closely related to the monoamine oxidase (MAO) enzyme, making it an attractive target for the exploitation of potent MAO inhibitors (MAOIs) with high selectivity and low side effects. Although various MAOIs have been discovered, the discovery of an ideal MAOI is not an easy task. In this review, we discuss the currently available rational design strategies for obtaining ideal MAOIs, including ligand-based and receptor-based design strategies, and these strategies were further illustrated with the aid of specific examples from the recent literature. To better understanding the biological activity of MAO, we also highlight the binding modes of typical inhibitors against MAO. Besides, advanced strategies for finding upcoming potent MAOIs were prospected.

Hybrid caffeic acid derivatives as monoamine oxidases inhibitors: synthesis, radical scavenging activity, molecular docking studies and in silico ADMET analysis

BackgroundMonoamine oxidase has been implicated in numerous neurological disorders. Although synthetic monoamine oxidase inhibitors (MAOI) have emerged with many side effects, the aspiration of natural based MAOI has greatly increased. As they exhibit fewer side effects and food interaction along with improved neuropharmacological profile.ResultsThe in silico design of the caffeic acid derivatives led potent MAO inhibitors with remarkable antioxidant activity. The mechanistic insight of the compounds within the hMAO active site was achieved by molecular docking which led us to be more confident of the possible inhibition of MAO.ConclusionsThe synthesized eugenol based ester of caffeic acid compound 7 exhibited MAO-A inhibition with IC50 values of 07.03 ± 0.022 µM with good selectivity (SI = 0.291) towards MAO-A. Conversely, two anilides compounds 2 and 1, bearing chloro and nitro group at 2, 4 positions showed MAO-A inhibition with IC50 values of 08.51 ± 0.017 µM and 08.87 ± 0.005 µM, respectively. Only one compound 5 was found as a significant MAO-B inhibitor with the IC50 value of 10.80 ± 0.024 µM. Moreover, compounds 1, 2, 4 and 9 have profoundly appeared as potent antioxidants as evaluated in duel assay by scavenging DPPH and H2O2.

Rhamnocitrin isolated from Prunus padus var. seoulensis: A potent and selective reversible inhibitor of human monoamine oxidase A

Three flavanones and two flavones were isolated from the leaves of Prunus padus var. seoulensis by the activity-guided screening for new monoamine oxidase (MAO) inhibitors. Among the compounds isolated, rhamnocitrin (5) was found to potently and selectively inhibit human MAO-A (hMAO-A, IC50 = 0.051 µM) and effectively inhibit hMAO-B (IC50 = 2.97 µM). The IC50 value of 5 for hMAO-A was the lowest amongst all natural flavonoids reported to date, and the potency was 20.2 times higher than that of toloxatone (1.03 µM), a marketed drug. In addition, 5 reversibly and competitively inhibited hMAO-A and hMAO-B with Ki values of 0.030 and 0.91 µM, respectively. Genkwanin (4) was also observed to strongly inhibit hMAO-A and hMAO-B (IC50 = 0.14 and 0.35 µM, respectively), and competitively inhibit hMAO-A and hMAO-B (Ki = 0.097 and 0.12 µM, respectively). Molecular docking simulation reveals that the binding affinity of 5 with hMAO-A (−18.49 kcal/mol) is higher than that observed with hMAO-B (0.19 kcal/mol). Compound 5 interacts with hMAO-A at four possible residues (Asn181, Gln215, Thr336, and Tyr444), while hMAO-B forms a single hydrogen bond at Glu84. These findings suggest that compound 5 as well as 4 can be considered as novel potent and reversible hMAO-A and/or hMAO-B inhibitors or useful lead compounds for future development of hMAO inhibitors in neurological disorder therapies.

In vitro anticholinesterase, antimonoamine oxidase and antioxidant properties of alkaloid extracts from kola nuts (Cola acuminata and Cola nitida).

Background The development of cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for management of neurodegenerative diseases such as Alzheimer's disease (AD) has come with their undesirable side effects. Hence, research for potent but natural ChE and MAO inhibitors with little or no side effects is essential. This study investigated the potentials of alkaloid extracts from two Cola species as nutraceuticals for prevention and management of AD. Methods Alkaloid extracts were obtained from two Cola species (Cola nitida [KN] and Cola acuminata [KA]) by solvent extraction method. The extracts were characterized for their alkaloid contents using gas chromatography (GC). The effects of the extracts on ChE and MAO activities were investigated in vitro. Also, the extracts' ability to inhibit Fe2+-induced lipid peroxidation in rat brain homogenate, scavenge DPPH and OH radicals, as well as chelate Fe2+ were determined. Results GC characterization revealed the presence of augustamine and undulatine as the predominant alkaloids in the extracts. There was no significant (P > 0.05) difference in the inhibitory effects of the extracts on ChE activities. However, KA extract exhibited significantly higher (P < 0.05) MAO inhibitory effect than KN. Also, KA extract inhibited Fe2+- induced malondialdehyde (MDA) production in rat brain homogenate more significantly than KN, while there was no significant difference in DPPH and OH radicals scavenging, as well as Fe2+-chelating abilities of the extracts. Conclusions Our findings revealed that KN and KA alkaloid extracts exhibited significant effect in vitro on biological pathways that may contribute to neuroprotection for the management of neurodegenerative diseases.

Synthesis and Evaluation of 2-benzylidene-1-tetralone Derivatives for Monoamine Oxidase Inhibitory Activity.

Chalcone has been identified as a promising lead for the design of Monoamine Oxidase (MAO) inhibitors. This study attempted to discover potent and selective chalcone-derived MAO inhibitors by synthesising a series consisting of various cyclic chalcone derivatives. The cyclic chalcones were selected based on the possibility that their restricted structures would confer a higher degree of MAO isoform selectivity, and included the following chemical classes: 1-indanone, 1- tetralone, 1-benzosuberone, chromone, thiochromone, 4-chromanone and 4-thiochromanone. The cyclic chalcone derivatives were synthesised via a one-pot Claisen-Schmidt condensation reaction. The MAO inhibitory properties of the chalcone derivatives were evaluated with the recombinant human MAO-A and MAO-B enzymes and the potencies were expressed as the IC50 values. A selected inhibitor was docked into an active site model of MAO-B. The results showed that the cyclic chalcones are in general good potency, and in most instances specific inhibitors of the MAO-B isoform. Among these compounds, the 4-chromanone derivative was the most potent MAO-B inhibitor with an IC50 value of 0.156 µM. To further investigate the MAO inhibition of cyclic chalcones, a series of twenty-three 2-benzylidene-1-tetralone derivatives were synthesised and evaluated as MAO inhibitors. Most 2-benzylidene-1-tetralones possess good inhibitory activity and specificity for MAO-B with the most potent inhibitor displaying an IC50 value of 0.0064 µM, while the most potent MAO-A inhibitor possessed an IC50 value of 0.754 µM. This study thus shows that certain cyclic chalcones are human MAO-B inhibitors, compounds that could be suitable for the treatment of neurodegenerative disorders such as Parkinson's disease.

Design, synthesis, in vitro and in silico evaluation of new pyrrole derivatives as monoamine oxidase inhibitors.

In an effort to develop potent monoamine oxidase (MAO) inhibitors, new pyrrole derivatives were obtained via the selective reduction of the CC bonds of 1-(1-methyl-1H-pyrrol-2-yl)-3-[5-(aryl)furan-2-yl]prop-2-en-1-ones through palladium catalyzed hydrogenation in ethanol. The synthesized compounds were screened for their inhibitory effects on MAO-A and MAO-B by an in vitro fluorometric method. The selectivity index (SI) value was given as the ratio of IC50 (MAO-A)/IC50 (MAO-B) for each compound. 3-(5-(4-Chlorophenyl)furan-2-yl)-1-(1-methyl-1H-pyrrol-2-yl)propan-1-one (6) was identified as the most selective MAO-A inhibitor in this series, with an IC50 value of 0.162 µM and a SI value of 0.002. Kinetic studies were also carried out to assess the nature of MAO-A inhibition by compound 6. According to Lineweaver-Burk plots, compound 6 was found to be a competitive MAO-A inhibitor and the Ki value of compound 6 was determined as 0.1221 μM. Docking studies were performed for compound 6 and clorgyline using the human MAO-A crystal structure (PDB ID: 2Z5Y). The docking results showed that compound 6 presented similar interactions as clorgyline in the active center cavity of the enzyme. Molinspiration software was used to determine the physicochemical parameters of all compounds for an evaluation of their compliance to Lipinski's rule of five. Compound 6 did not violate Lipinski's rule, making it a potential orally bioavailable therapeutic agent.

Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson’s disease therapy

Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC50: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAO-B inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson’s disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.

The relation between isatin and selegiline by the alteration of serum isatin, an endogenous monoamine oxidase inhibitor, induced by selegiline hydrochloride in Parkinson's disease

Background: Monoamine oxidase (MAO) is an enzyme that metabolizes a wide range of monoamines and play an important role in the control of neurotransmitter concentrations. However, the detailed CNS functions of an endogenous MAO inhibitor, isatin, were not determined. Isatin was found to be a potent MAO inhibitor that is more active against MAO-B than MAO-A. Exogenously administered isatin increased dopamine (DA) levels in the rat striatum. Furthermore isatin improves motor dysfunction and the DA levels in the striatum in rat model of Parkinson’s disease(Ogata et al., 2003). We showed the low concentration in the serum isatin was found in Parkinson's disease patients as compared with controls.

Synthesis and structure-activity relationship study of novel 3-heteroarylcoumarins based on pyridazine scaffold as selective MAO-B inhibitors

Compounds of hybrid structure pyridazine-coumarin were discovered as potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B). These compounds were synthesized in good yield following a multistep approach based on Knoevenagel reaction and using as key intermediate pyridazinone 16, which was obtained from maleic anhydride and furan. Compounds 9b and 9d are the most active compounds of these series, with IC50 values in the sub-micromolar range, and lack of cytotoxic effects. Theoretical calculation of ADME properties also suggested a good pharmacokinetic profile for both compounds.Docking simulations provided insights into enzyme inhibitor interactions and allowed us to rationalize the observed structure-activity relationships (SARs).

Potent Inhibition of Monoamine Oxidase B by a Piloquinone from Marine-Derived Streptomyces sp. CNQ-027.

Two piloquinone derivatives isolated from Streptomyces sp. CNQ-027 were tested for the inhibitory activities of two isoforms of monoamine oxidase (MAO), which catalyzes monoamine neurotransmitters. The piloquinone 4,7-dihydroxy-3-methyl-2-(4-methyl-1-oxopentyl)-6H-dibenzo[b,d]pyran-6-one (1) was found to be a highly potent inhibitor of human MAO-B, with an IC50 value of 1.21 µ; in addition, it was found to be highly effective against MAO-A, with an IC50 value of 6.47 µ. Compound 1 was selective, but not extremely so, for MAO-B compared with MAO-A, with a selectivity index value of 5.35. Compound 1,8-dihydroxy-2-methyl-3-(4-methyl-1-oxopentyl)-9,10-phenanthrenedione (2) was moderately effective for the inhibition of MAO-B (IC50 = 14.50 µ) but not for MAO-A (IC50 > 80 µ). There was no time-dependency in inhibition of MAO-A or -B by compound 1, and the MAO-A and -B activities were almost completely recovered in the dilution experiments with an excess amount of compound 1. Compound 1 showed competitive inhibition for MAO-A and -B, with Ki values of 0.573 and 0.248 µ, respectively. These results suggest that piloquinones from a microbial source could be potent reversible MAO inhibitors and may be useful lead compounds for developing MAO enzyme inhibitors to treat related disorders, such as depression, Parkinson's disease, and Alzheimer's disease.

The evaluation of 1,4-benzoquinones as inhibitors of human monoamine oxidase

The monoamine oxidase (MAO) enzymes are of considerable pharmacological interest and inhibitors are used in the clinic for the treatment of major depressive disorder and Parkinson's disease. A limited number of studies have shown that the quinone class of compounds possesses MAO inhibition properties. Most notable among these is a report that 2,3,6-trimethyl-1,4-naphthoquinone (TMN), present in extracts of cured tobacco leafs, is a non-selective inhibitor of both MAO isoforms. An older study reports that 1,4-benzoquinone inhibits MAO-A and MAO-B from human synaptosomes. Both 1,4-naphthoquinones and 1,4-benzoquinone are reported to inhibit the MAOs with a reversible mode of action. Since the MAO inhibition properties of additional members of the 1,4-benzoquinone class of compounds have not yet been explored, the present study investigates a small series of four 1,4-benzoquinones which incorporate phenyl, benzyl, benzyloxy and cyclopentyl monosubstitution on C2. The 1,4-benzoquinones were found to be moderately potent MAO inhibitors with IC50 values of 5.03–13.2 μM (MAO-A) and 3.69–23.2 μM (MAO-B). These values are comparable to those recorded for 1,4-benzoquinone of 4.82 μM (MAO-A) and 10.2 μM (MAO-B). Of interest however, is the finding that the 1,4-benzoquinones are irreversible inhibitors of MAO-A since prolonged incubation results in near complete inhibition, and enzyme activity is not recovered by dialysis. MAO-B is much less sensitive to inactivation by the 1,4-benzoquinones. These findings are discussed with reference to a possible mechanism by which irreversible inhibition occurs. It may be concluded that irreversible 1,4-benzoquinone-derived inhibitors may act as probes for investigating quinone reactive sites in the MAOs.

Structure-Based Design and Synthesis of Harmine Derivatives with Different Selectivity Profiles in Kinase versus Monoamine Oxidase Inhibition.

Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome, in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases, could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand, harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design, we synthesized a collection of harmine analogues with tunable selectivity toward these two enzymes. Modifications at the 7-position typically decreased affinity for DYRK1A, whereas substitution at the 9-position had a similar effect on MAO-A inhibition but DYRK1A inhibition was maintained. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO-A inhibition.

The monoamine oxidase inhibition properties of selected structural analogues of methylene blue

The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC50=0.0037μM), Nile blue (IC50=0.0077μM) and 1,9-dimethyl methylene blue (IC50=0.018μM) exhibiting higher potency inhibition compared to MB (IC50=0.07μM). Nile blue also represents a potent MAO-B inhibitor with an IC50 value of 0.012μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST.

Potent Selective Inhibition of Monoamine Oxidase A by Alternariol Monomethyl Ether Isolated from Alternaria brassicae.

Alternariol monomethyl ether (AME), a dibenzopyrone derivative, was isolated from Alternaria brassicae along with altertoxin II (ATX-II). The compounds were tested for the inhibitory activity of monoamine oxidase (MAO), which catalyzes neurotransmitting monoamines. AME was found to be a highly potent and selective inhibitor of human MAO-A with an IC50 value of 1.71 µM; however, it was found to be ineffective for MAO-B inhibition. ATX-II was not effective for the inhibition of either MAO-A or MAO-B. The inhibition of MAO-A using AME was apparently instantaneous. MAO-A activity was almost completely recovered after the dilution of the inhibited enzyme with an excess amount of AME, suggesting AME is a reversible inhibitor. AME showed mixed inhibition for MAO-A in Lineweaver-Burk plots with a Ki value of 0.34 µM. The findings of this study suggest that microbial metabolites and dibenzopyrone could be potent MAO inhibitors. In addition, AME could be a useful lead compound for developing reversible MAO-A inhibitors to treat depression, Parkinson's disease, and Alzheimer's disease.

Characterization of 1-Aminobenzotriazole and Ketoconazole as Novel Inhibitors of Monoamine Oxidase (MAO): An In Vitro Investigation.

1-Aminobenzotriazole, a known time-dependent inhibitor of cytochrome P450 (CYP) enzymes, and ketoconazole, a strong inhibitor of the human CYP3A4 isozyme, are used as standard probe inhibitors to characterize the CYP and/or non-CYP-mediated metabolism of xenobiotics. In the present investigation, 1-Aminobenzotriazole and ketoconazole are characterized as potent monoamine oxidase (MAO) inhibitors in vitro using mouse, rat and human liver microsomes and S9 fractions. Inhibition potential of 1-aminobenzotriazole and ketoconazole was studied in mice, rat and human liver microsomes, S9 fractions, MAO-A and MAO-B expressed enzymes by monitoring the formation of 4-hydroxyquinoline (4-HQ) from kynuramine, a specific substrate of MAO by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Mechanism of MAO inhibition was studied by incubating varying concentration of kynuramine with mouse, rat and human S9 fractions at varying concentration of 1-aminobenzatriazole and ketoconazole and monitoring the formation of 4-HQ. 1-aminobenzotriazole and ketoconazole inhibited both MAO isozymes (MAO-A and MAO-B) with more specificity towards MAO-B. Kynuramine substrate kinetics in mouse, rat and human S9 fractions with varying 1-aminobenzotriazole and ketoconazole concentrations showed decreased maximum rate (V max) for 4-HQ formation without affecting theMichaelis-Menten constant (K m). A non-competitive inhibition model was constructed and inhibition constants (K i) for 1-aminobenzotriazole (7.87±0.61, 8.61±0.92, 65.2±1.61µM for mice, rat and humans, respectively) and ketoconazole (0.12±0.01, 2.04±0.08, 5.52±0.47µM for mice, rat and humans, respectively) were determined. 1-Aminobenzotriazole and ketoconazole are characterized as non-competitive inhibitors of mice, rat and human MAO in vitro and the extent of their MAO inhibition potential is species specific. 1-Aminobenzotriazole or ketoconazole can be used as a probe inhibitor in vitro for screening the involvement of MAO-dependent metabolism of new chemical entities (NCE) in early drug discovery.

Synthesis and pharmacological evaluation of multi-functional homoisoflavonoid derivatives as potent inhibitors of monoamine oxidase B and cholinesterase for the treatment of Alzheimer's disease.

A series of homoisoflavonoid derivatives was designed, synthesized and evaluated as potential multi-functional anti-Alzheimer's agents for their inhibitory activity on cholinesterase and monoamine oxidase. Among them, compound 16 showed moderate acetylcholinesterase (AChE) inhibitory activity (eeAChE IC50 = 0.89 ± 0.02 μM; hAChE IC50 = 0.657 ± 0.002 μM) and significant monoamine oxidase B (MAO-B) inhibitory activity (hMAO-B IC50 = 0.0372 ± 0.0002 μM). Kinetic analysis of AChE, MAO-B inhibition and molecular modeling studies revealed that compound 16 is a dual binding site inhibitor of AChE and noncompetitive inhibitor of MAO-B. Furthermore, 16 could penetrate through the blood-brain barrier (BBB) in vitro. Most importantly, oral administration of 16 demonstrated no marked signs of acute toxicity and it could significantly reverse scopolamine-induced memory impairment in mice. These results suggested that compound 16 is a promising multifunctional drug candidate with potential effect for the treatment of Alzheimer's disease.

Synthesis and evaluation of small molecules bearing a benzyloxy substituent as novel and potent monoamine oxidase inhibitors.

A new series of small molecules bearing a benzyloxy substituent have been designed, synthesized and evaluated for hMAO inhibitory activity in vitro. Most of the compounds were potent and selective MAO-B inhibitors, and were weak inhibitors of MAO-A. In particular, compounds 9e (IC50 = 0.35 μM) and 10e (IC50 = 0.19 μM) were the most potent MAO-B inhibitors, and exhibited the highest selectivity for MAO-B (9e, SI > 285.7-fold and 10e, SI = 146.8-fold). In addition, the structure-activity relationships for MAO-B inhibition indicated that electron-withdrawing groups in the open small molecules were more suitable for MAO-B inhibition, and substitutions at the benzyloxy of the open small molecules, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking studies have been done to explain the potent MAO-B inhibition of the open small molecules. Furthermore, the representative compounds 9e and 10e showed low neurotoxicity in SH-SY5Y cells in vitro. So the small molecules bearing the benzyloxy substituent could be used to develop promising drug candidates for the therapy of neurodegenerative diseases.

Through scaffold modification to 3,5-diaryl-4,5-dihydroisoxazoles: new potent and selective inhibitors of monoamine oxidase B

3,5-Diaryl-4,5-dihydroisoxazoles were synthesized and evaluated as monoamine oxidase (MAO) enzyme inhibitors and iron chelators. All compounds exhibited selective inhibitory activity towards the B isoform of MAO in the nanomolar concentration range. The best performing compound was preliminarily evaluated for its ability to bind iron II and III cations, indicating that neither iron II nor iron III is coordinated. The best compounds racemic mixtures were separated and single enantiomers inhibitory activity evaluated. Furthermore, none of the synthesised compounds exhibited activity towards MAO A. Overall, these data support our hypothesis that 3,5-diaryl-4,5-dihydroisoxazoles are promising scaffolds for the design of neuroprotective agents.

Benzyloxynitrostyrene analogues – A novel class of selective and highly potent inhibitors of monoamine oxidase B

This study examines a series of novel 3-benzyloxy-β-nitrostyrene analogues as a novel class of inhibitors of the monoamine oxidase (MAO) enzymes. MAO inhibitors are considered useful for the treatment of depression and Parkinson's disease, and have recently attracted attention as potential therapeutic agents for a range of disorders including Alzheimer's disease, prostate cancer and certain cardiomyopathies. This study shows that the 3-benzyloxy-β-nitrostyrene analogues are potent inhibitors of the MAO-B isoform with IC50 values in the nanomolar range (39–565 nM). Significantly, effectiveness towards MAO-B inhibition seems to be governed by the introduction of a 4″-fluoro-substituent on the benzyloxy ring, with compound 2b exhibiting the highest degree of MAO-B inhibition potency (IC50 = 0.039 μM) and selectivity (SI = 166) among the compounds investigated. Since some of the 3-benzyloxy-β-nitrostyrene analogues possess potencies that are comparable to that of the reversible inhibitor, safinamide (IC50 = 0.080 μM), it may be concluded that this class may be promising leads for the development of reversible and selective MAO-B inhibitors, that may be useful for the management of Parkinson's disease.

Rapid synthesis of flavone-based monoamine oxidase (MAO) inhibitors targeting two active sites using click chemistry.

A new library of flavone derivatives targeting two active sites of monoamine oxidases ("aromatic cage" and substrate cavity) were designed and synthesized using click chemistry (CuAAC reaction) between 6-N3 -2-phenyl chromones (Az1-Az2) and a series of alkynes (k1-k20). Their inhibitory activities against MAO isoforms (MAO-A and MAO-B) are evaluated. Compounds with fluorine, amide bonds, or amino bonds have shown better inhibition. The most potent flavone MAO inhibitor studied is Az2k19 (1.6μm for MAO-A, 2.1μm for MAO-B), while Az1k15 and Az2k15 displayed better selectivity toward MAO-B (SI>10). Docking studies are in accordance with our hypothesis that these inhibitors are most likely located at both the substrate cavity and the "aromatic cage". Our results show that it is considerable to develop new MAO inhibitors from C6 substitution of flavone derivatives and that these compounds are also potential for the treatment of diseases associated with MAOs.