Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of N,N'-bis[2-oxo-2H-benzopyran]-3-carboxamides

A novel series of N,N'-bis[2-oxo-2H-1-benzopyran]-3-carboxamide derivatives have been synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). Some of the synthesized compounds show good selective inhibitory activity against the MAO-A isoform. Both the MAO-A and -B isoforms, deposited in the Protein Data Bank as the 2BXR and 1GOS models, respectively, were considered in a computational study performed with docking techniques on the most active and selective inhibitors.     

Synthesis of some novel hydrazone and 2-pyrazoline derivatives: Monoamine oxidase inhibitory activities and docking studies

A novel series of 2-pyrazoline and hydrazone derivatives were synthesized and investigated for their human monoamine oxidase (hMAO) inhibitory activity. All compounds inhibited the hMAO isoforms (MAO-A or MAO-B) competitively and reversibly. With the exception of 5i, which was a selective MAO-B inhibitor, all derivatives inhibited hMAO-A potently and selectively. According to the experimental K_i values, compounds 6e and 6h exhibited the highest inhibitory activity towards the hMAO-A, whereas compound 5j, which carries a bromine atom at R⁴ of the A ring of the pyrazoline, appeared to be the most selective MAO-A inhibitor. Tested compounds were docked computationally into the active site of the hMAO-A and hMAO-B isozymes. The computationally obtained results were in good agreement with the corresponding experimental values.     

Monoamine oxidase A and B inhibiting effect and molecular modeling of some synthesized coumarin derivatives

New series of bioactive 7-oxycoumarin derivatives were synthesized and tested for their in vitro and in vivo monoamine oxidase (MAO) A and B inhibitory effect. In vitro studies revealed exceptionally potent and selective MAO-A inhibitors with K_i values on a picomolar range. The acetohydrazide (3b) and the dioxopyrrolidine derivative (7b) showed the most potent in vitro and in vivo MAO inhibition activity. Moreover, molecular modeling study of the synthesized compounds into MAO-A (PDB: 2Z5X) and MAO-B (PDB: 2XFN) binding sites exhibited direct correlation between AutoDock binding affinity and% inhibition MAO-A (pM) and MAO-B (μM). In addition, the results of in vivo MAO inhibiting properties (ED₅₀) of the tested compounds revealed better direct correlation.     

Synthesis and inhibitory effect of piperine derivates on monoamine oxidase

A series of piperine derivates (1-19) have been designed, synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. It is worth noting that most of the small amine moieties substituted on the piperidine ring proved to be potent and selective inhibitors of MAO-B rather than of MAO-A. 5-(3,4-methylenedioxyphenyl)-2E,4E-pentadienoic acid n-propyl amide (3) showed the greatest MAO-B inhibitory activity (IC(50)(MAO-B)=0.045 μM) and good selectivity (IC(50)(MAO-A)=3.66 μM). The conjugated double bond and carbonyl group of piperine are proved to be an essential feature for piperine and related alkylamides to exhibit MAO-inhibitory activity. Binding mode of the titled compounds was predicted using FlexX algorithm. The design and optimization of novel small molecule monoamine oxidase inhibitors will be guided by the results of this report.     

Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors

Previous studies have shown that harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with harmine has been recently solved. This crystal structure shows that close to the methoxy group of the harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the ??-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of ??-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their K_i values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a K_i against MAO-A of 3.6 nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a K_i value of 221.6 nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a K_i value of 4.3 nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.     

Inhibition of monoamine oxidase-A activity in rat brain by synthetic hydrazines: structure-activity relationship (SAR)

A series of hydrazine derivatives was synthesized in order to evaluate their monoamine oxidase A (MAO-A) inhibitory effects. MAO-A inhibitory activity of 4-tosyl benzoic acid carbohydrazide was quite potent, similarly to that of the corresponding 4-benzyloxy-benzoic acid carbohydrazide and its N-cyanoethylated derivative. Structural variations of these compounds, such as the replacement of the 4-substitutent, of the aromatic ring on which the carbohydrazide moiety is grafted, as well as cyclization of the hydrazide moiety in five- or six-membered rings caused either significant decline or complete loss of MAO inhibitory properties. The most active compound (4-tosyl benzoic acid carbohydrazide) was also subjected to the forced swim test, an animal model of depression, eliciting a marked reduction in immobility time in rats, without affecting the locomotor activity, implying that it possesses anti-depressant properties due to inhibition of MAO type-A.     

Inhibition of monoamine oxidase–A activity in rat brain by synthetic hydrazines: Structure-activity relationship (SAR)

A series of hydrazine derivatives was synthesized in order to evaluate their monoamine oxidase A (MAO-A) inhibitory effects. MAO-A inhibitory activity of 4-tosyl benzoic acid carbohydrazide was quite potent, similarly to that of the corresponding 4-benzyloxy-benzoic acid carbohydrazide and its N-cyanoethylated derivative. Structural variations of these compounds, such as the replacement of the 4-substitutent, of the aromatic ring on which the carbohydrazide moiety is grafted, as well as cyclization of the hydrazide moiety in five- or six-membered rings caused either significant decline or complete loss of MAO inhibitory properties. The most active compound (4-tosyl benzoic acid carbohydrazide) was also subjected to the forced swim test, an animal model of depression, eliciting a marked reduction in immobility time in rats, without affecting the locomotor activity, implying that it possesses anti-depressant properties due to inhibition of MAO type-A.     

Synthesis and evaluation of aplysinopsin analogs as inhibitors of human monoamine oxidase A and B

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities, including modulation of neurotransmissions. A series of fifty aplysinopsin analogs was synthesized and assayed for monoamine oxidase A and B inhibitory activity. Three compounds displayed significant MAO inhibitory activity and selectivity. The compound (E)-5-[(6-bromo-1H-indol-3-yl)methylene]-2-imino-1,3-dimethylimidazolidin-4-one (3x) possessed an IC(50) of 5.6 nM at MAO-A and had a selectivity index of 80.24. An SAR study revealed that multiple N-methylations, one of which should be at position N-2', and bromination at C-5 or C-6 are important factors for MAO-A potency and selectivity.     

A new series of flavones,thioflavones, and flavanones as selective monoamine oxidase-B inhibitors

A new series of synthetic flavones, thioflavones, and flavanones has been synthesized and evaluated as potential inhibitors of monoamine oxidase isoforms (MAO-A and -B). The most active series is the flavanone one with higher selective inhibitory activity against MAO-B. Some of these flavanones (mainly the most effective) have been separated and tested as single enantiomers. In order to investigate the MAOs recognition of the most active and selective compounds, a molecular modeling study has been performed using available Protein Data Bank (PDB) structures as receptor models for docking experiments.     

MAO inhibitory activity modulation: 3-Phenylcoumarins versus 3-benzoylcoumarins

With the aim of finding the structural features for the human MAO inhibitory activity and selectivity, in the present communication we report the synthesis, pharmacological evaluation and a comparative study of a new series of 3-phenylcoumarins (compounds 1-4) and 3-benzoylcoumarins (compounds 5-8). A bromo atom and a methoxy/hydroxy substituent were introduced in these scaffolds, at six and eight positions of the coumarin moiety, respectively. The synthesized compounds 1-8 were evaluated as MAO-A and B inhibitors using R-(−)-deprenyl and iproniazide as reference compounds. The presence or absence of a carbonyl group between the coumarin and the phenyl substituent in 3 position remarks, respectively, the MAO-A or MAO-B inhibitory activity. Some of the new compounds showed MAO-B inhibitory activities in the low nanomolar range. Compound 2 (IC₅₀ = 1.35 nM) showed higher inhibitory activity than the R-(−)-deprenyl (IC₅₀ = 19.60 nM) and higher MAO-B selectivity, with more than 74,074-fold inhibition level, respecting to the MAO-A isoform.     

Novel 1-(2-pyrimidin-2-yl)piperazine derivatives as selective monoamine oxidase (MAO)-A inhibitors

In the present study, a new series of 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-substituted piperazine-1-carbodithioate derivatives (2a-n) were synthesized and screened for their monoamine oxidase A and B inhibitory activity. The structures of compounds were elucidated using spectroscopic methods and some physicochemical properties of new compounds were predicted using Molinspiration and MolSoft programs. Compounds 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-(4-nitrophenyl)piperazine-1-carbodithioate (2j) and 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-benzhydrylpiperazine-1-carbodithioate (2m) exhibited selective MAO-A inhibitory activity with IC_50?=_?23.10, 24.14?µM, respectively. Some of the biological results were found in accordance with the obtained in silico data based on Lipinski’s fule of five.     

Lipophilicity plays a major role in modulating the inhibition of monoamine oxidase B by 7-substituted coumarins

A series of coumarin derivatives (1-22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC(50) values in the micromolar to low-nanomolar range. A structure-activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r(2)=0.72) between pIC(50) and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1 h after intraperitoneal administration of high doses (100 and 300 mumol kg(-1)), revealing its ability to cross the blood-brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues.     

Design of novel nicotinamides as potent and selective monoamine oxidase a inhibitors

A series of N-(2-morpholinoethyl)nicotinamide (1–13) and N-(3-morpholinopropyl)nicotinamide derivatives (14–26) have been designed, synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. Most of these synthesized compounds proved to be potent, and selective inhibitors of MAO-A rather than of MAO-B. 5-Chloro-6-hydroxy-N-(2-morpholinoethyl)nicotinamide (13) displayed the highest MAO-A inhibitory potency (IC₅₀ = 0.045 μM) and a good selectivity. 2-Bromo-N-(2-morpholinoethyl)nicotinamide (3) was the most potent MAO-B inhibitor with the IC₅₀ value of 0.32 μM, but it was not selective. Molecular dockings of compound 13 were performed in order to give structural insights regarding the MAO-A selectivity.     

Synthesis of some novel 2-substituted benzothiazole derivatives containing benzylamine moiety as monoamine oxidase inhibitory agents

In the present work, 12 new 2-(5-substituted-benzothiazol-2-ylsulfanyl)-N-(substitutedbenzyl)-N-(4-substitutedphenyl) acetamide derivatives (4a–l) was designed and synthesized. The structures of the synthesized compounds were clarified using Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (¹H-NMR), carbon-13 nuclear magnetic resonance (¹³C-NMR) and high-resolution mass spectrometry (HRMS) spectral data. Purity of synthesized compounds was checked by high-performance liquid chromatography (HPLC) analyses and purity ratio was found between 96.5–99.9%. The inhibitory activity of the compounds against MAO-A and MAO-B enzymes was evaluated by using in vitro flurometric method in which kynuramine was used as a substrate. Most of the compounds exhibited more selective inhibitory activity towards monoamine oxidase B (MAO-B) than monoamine oxidase A (MAO-A). Compound 4h was determined as the most potent compound against both enzyme types. The MAO-B enzyme kinetic of the compound 4h was studied and nature of MAO-B inhibition, caused by this compound, was investigated. The graphical analysis of steady-state inhibition data indicated that compound 4h is a mixed type inhibitor. Theoretical calculation of absorption, distribution, metabolism, excretion (ADME) properties for the synthesized compounds was also carried out and observed data supported the potential of compound 4h.     

Design,synthesis and biological evaluation of lazabemide derivatives as inhibitors of monoamine oxidase

In the studied a series novel of lazabemide derivatives were designed, synthesized and evaluated as inhibitors of monoamine oxidase (MAO-A or MAO-B). These compounds used lazabemide as the lead compound, and the chemistry structures were modified by used the bioisostere and modification of compound with alkyl principle. The two types of inhibitors (inhibition of MAO-A and inhibition of MAO-B) were screened by inhibition activity of MAO. In vitro experiments showed that compounds 3a, 3d and 3f had intensity inhibition the biological activity of MAO-A, while compounds 3i and 3m had intensity inhibition the biological activity of MAO-B. It could be seen from the data of inhibition activity experiments in vitro, that the compound 3d was IC₅₀?=?3.12?±?0.05?μmol/mL of MAO-A and compound 3m was IC₅₀?=?5.04?±?0.06?μmol/mL. In vivo inhibition activity experiments were conducted to evaluate the inhibitory activity of compounds 3a, 3d, 3f, 3i and 3m by detecting the contents of 5-HT, NE, DA and activity of MAO-A and MAO-B in plasma and brain tissue. In vivo inhibition activity evaluation results showed that the compounds 3a, 3d, 3f, 3i and 3m had increased the contents of 5-HT, NE and DA in plasma and brain tissues. Meanwhile, the determination results activity of MAO in plasma and brain tissue showed that the compounds 3a, 3d, and 3f had a significant inhibitory effect on the activity of MAO-A, while the compounds 3i and 3m showed inhibitory effect on the activity of MAO-B. This study provided a new inhibitors for inhibiting of MAO activity.     

Synthesis and acrosin inhibitory activity of methyl 5-substituted-1H-benzo[d]imidazol-2-yl carbamate derivatives

A series of novel methyl 5-substituted 1H-benzo[d]imidazol-2-ylcarbamates were designed, synthesized, and their acrosin inhibitory activities evaluated in vitro. The results of acrosin inhibitory activity showed that all title compounds were more potent than the control TLCK. Compound 4w displayed the most potent acrosin inhibitory activity among all the compounds, with an IC(50) of 6.3×10(-5)M. The studies provide a new structural class for the development of novel acrosin inhibitory agents.     

Design,synthesis and biological evaluation of type-II VEGFR-2 inhibitors based on quinoxaline scaffold

In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a series of new quinoxaline-based derivatives was designed and synthesized. The target compounds were biologically evaluated for their inhibitory activity against VEGFR-2. The design of the target compounds was accomplished after a profound study of the structure activity relationship (SAR) of type-II VEGFR-2 inhibitors. Among the synthesized compounds, 1-(2-((4-methoxyphenyl)amino)-3-oxo-3,4 dihydroquinoxalin-6-yl)-3-phenylurea (VIIa) displayed the highest inhibitory activity against VEGFR-2. Molecular modeling study involving molecular docking and field alignment was implemented to interpret the variable inhibitory activity of the newly synthesized compounds.     

Design, synthesis, and biological evaluation of substituted hydrazone and pyrazole derivatives as selective COX-2 inhibitors: Molecular docking study

New arylhydrazone derivatives and a series of 1,5-diphenyl pyrazoles were designed and synthesized from 1-(4-chlorophenyl)-4,4,4-trifuorobutane-1,3-dione 1. The newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw oedema model. Moreover, they were tested for their inhibitory activity against ovine COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Some of the new compounds (2f, 6a and 6d) showed a reasonable in vitro COX-2 inhibitory activity, with IC?? value of 0.45 μM and selectivity index of 111.1. A virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Docking study of the synthesized compounds 2f, 6a and 6d into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.     

Design and synthesis of 3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-quinolin-2-ones as VEGFR-2 kinase inhibitors

A series of 3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-quinolin-2-ones have been identified as a new class of VEGFR-2 kinase inhibitors. A variety of (4,5,6,7-tetrahydro-imidazo[5,4-c]pyridin-2-yl)-acetic acid ethyl esters were synthesized, and their VEGFR-2 inhibitory activity was evaluated. Described herein are the preparation of the series and the effects of the compounds on VEGFR-2 kinase activity.     

In vitro and in silico evaluation of new thiazole compounds as monoamine oxidase inhibitors

New twenty compounds bearing thiazole ring (3a-3t) were designed and synthesized as monoamine oxidase (MAO) inhibitors. The fluorometric enzyme inhibition assay was used to determine the biological effects of synthesized compounds. Most of them showed remarkable inhibitory activity against both MAO-A and MAO-B. By comparing their IC₅₀ values, it can be seen that active derivatives displayed generally selectivity on MAO-B enzyme. Compounds 3j and 3t, which bear dihydroxy moiety at the 3rd and 4th position of phenyl ring, were the most active derivatives in the series against both isoenzymes. Compounds 3j and 3t showed significant inhibition profile on MAO-A with the IC₅₀ values of 0.134 ± 0.004 µM and 0.123 ± 0.005 µM, respectively, while they performed selectivity against MAO-B with the IC₅₀ values of 0.027 ± 0.001 µM and 0.025 ± 0.001 µM, respectively. Also, docking studies about these compounds were carried out to evaluate their binding modes on the active regions of MAO-A and MAO-B.