次黄嘌呤对单胺氧化酶的抑制作用

实验证明给小鼠po次黄嘌呤25～500 mg/kg时,对肝和脑中单胺氧化酶B(MAOB)活性的抑制作用与剂量成明显的量—效关系,对MAO-A活性的抑制较弱,且无明显的量—效关系。给小鼠一次po次黄嘌呤500 mg/kg,于给药后16h,对MAO抑制作用最明显。sc时,对肝中MAO活性抑制也以给药后16 h最明显,但对脑中MAO活性抑制不明显。离体实验证明,次黄嘌呤对MAO-B的抑制为竞争性,对MAO-A则为混合型抑制。     

Inhibition of rat brain monoamine oxidase activities by psoralen and isopsoralen: implications for the treatment of affective disorders

Psoralen and isopsoralen, furocoumarins isolated from the plant Psoralea corylifolia L., were demonstrated to exhibit in vitro inhibitory actions on monoamine oxidase (MAO) activities in rat brain mitochondria, preferentially inhibiting MAO-A activity over MAO-B activity. This inhibition of enzyme activities was found to be dose-dependent and reversible. For MAO-A, the IC50 values are 15.2 +/- 1.3 microM psoralen and 9.0 +/- 0.6 microM isopsoralen. For MAO-B, the IC50 values are 61.8 +/- 4.3 microM psoralen and 12.8 +/- 0.5 microM isopsoralen. Lineweaver-Burk transformation of the inhibition data indicates that inhibition by both psoralen and isopsoralen is non-competitive for MAO-A. The Ki values were calculated to be 14.0 microM for psoralen and 6.5 microM for isopsoralen. On the other hand, inhibition by both psoralen and isopsoralen is competitive for MAO-B. The Ki values were calculated to be 58.1 microM for psoralen and 10.8 microM for isopsoralen. These inhibitory actions of psoralen and isopsoralen on rat brain mitochondrial MAO activities are discussed in relation to their toxicities and their potential applications to treat affective disorders.     

Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 μM) and BuChE (IC50=0.46±0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.     

Enzymic and molecular characteristics of a new form of monoamine oxidase, distinct from form-A and form-B

The present study was undertaken to clarify the enzymic and molecular properties of monoamine oxidase (MAO) in carp brain. In particular, its sensitivities to selective MAO inhibitors, kinetic properties and molecular weight were compared with those of the enzyme in carp liver. The selective and potent MAO-A and MAO-B inhibitors FLA 788(+), FLA 336(+), MD 780236 and benzylcyanide caused dose-dependent inhibitions of MAO activity in both carp brain and liver; the inhibition curves were all single-sigmoidal, and the degrees of inhibition of the activities towards 5-hydroxytryptamine (5-HT, selective MAO-A substrate), tyramine (substrate for both forms of MAO) and beta-phenylethylamine (PEA, selective MAO-B substrate) were similar. This was also the case for inhibition of activity in carp brain by the irreversible and selective MAO-A and MAO-B inhibitors clorgyline and I-deprenyl, indicating the presence in both preparations of a single MAO which differs from either form of MAO. Studies on the substrate specificities and Km values for these three substrates and the inhibitory effects of some compounds suggested that the enzymic characters of MAO in carp preparations were similar and that these enzymes might be FAD-containing enzymes, like MAO in various mammals. By labelling the preparations with radioactive pargyline and then subjecting them to sodium dodecyl sulfate electrophoresis, the apparent molecular weights of carp brain and liver MAO were estimated as 60,000 daltons. The same value was also obtained for rat brain and liver mitochondrial MAO-B. These results indicate that by the present definitions of MAO-A and MAO-B, MAO in carp brain and liver is similar to, but distinct from, both these forms of MAO.     

Inhibition of rat platelet 5-hydroxytryptamine uptake by chlorpyrifos and carbaryl

The organophosphate insecticide chlorpyrifos and the carbamate insecticide carbaryl were investigated in adult male rats in terms of their effects on the activity of brain monoamine oxidase-A (MAO-A) activity and on the platelet uptake of 5-hydroxytryptamine (5-HT). The activities of brain acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) were also determined. For each compound two different dosage regimens were employed. In the acute study, chlorpyrifos or carbaryl was administered at a single intraperitoneal dose of 100 mg/kg or 50 mg/kg, respectively In the subacute study, chlorpyrifos was injected at a daily dose of 20 mg/kg for 7 days, while carbaryl was given at a daily dose of 10 mg/kg for 14 days. Acute chlorpyrifos administration produced a 85.01% inhibition of AChE and a 43.4% inhibition of BuChE but had no effect on MAO-A activity and 5-HT uptake. In contrast, subacute chlorpyrifos exposure caused a 94.96% inhibition of AChE and a 85.8% inhibition of BuChE and, also, elicited a significant (35.02%) reduction in the platelet uptake of 5-HT. MAO-A activity was not affected. Acute carbaryl administration produced a 56.38% AChE inhibition and a 55.95% BuChE inhibition and also caused a significant (26.36%) decrease in 5-HT uptake but no change in MAO-A. Subacute carbaryl exposure failed to affect significantly any of the biochemical parameters determined. Interference with the 5-HT system by chlorpyrifos and carbaryl could contribute to the toxicity of these pesticides.     

Methylpiperate derivatives from Piper longum and their inhibition of monoamine oxidase

We have previously reported that piperine, a known piperidine alkaloid from Piper longum, competitively inhibited mouse brain MAO-A and MAO-B activities. Piperine also showed in vivo antidepressant-like activity against the tail suspension test. In the present study, we further expanded on the identification of MAO inhibitors from the fruit of P. longum. Activity-guided fractionation of a methylene chloride soluble extract led to the isolation of three known piperine-related compounds, methylpiperate (1), guineensine (2), and piperlonguminine (3). Of these, methylpiperate (1) and guineensine (2) showed significant MAO inhibitory activities with IC50 values of 3.6 and 139.2 microM, respectively. Furthermore, methylpiperate (1) exhibited a selective inhibitory effect against MAO-B (IC50 value: 1.6 microM) than MAO-A (IC50 value: 27.1 microM). The kinetic study using the Lineweaver-Burk plots analysis suggested that methylpiperate (1) competitively inhibits MAO-A and MAO-B activities with the Ki values of 23.5 and 1.3 microM, respectively.     

An in vitro interethnic comparison of monoamine oxidase activities between Japanese and Caucasian livers using rizatriptan, a serotonin receptor 1B/1D agonist, as a model drug

AIMS: Monoamine oxidase (MAO) is located in human liver, and catalyses the oxidative deamination step of many xenobiotics. However, whether there exists an interethnic difference in MAO activities has, to our knowledge, not been clarified. We aimed to assess the MAO type A (MAO-A) involvement in the metabolic pathway of rizatriptan (RIZ), an antimigraine 5-hydroxytryptamine (5-HT)1B/1D agonist, and the interethnic difference in MAO activities between Caucasians and Japanese using RIZ as a model drug in in vitro experiments. METHODS: Oxidative deaminase activities were determined with the subcellular fractions of Japanese livers and the microsomal fraction of Caucasian livers using RIZ, 5-HT (MAO-A substrate) and 2-phenylethylamine (PEA) (MAO-B substrate) as substrates. RESULTS: The oxidative deaminase activities of RIZ vs. 5-HT were highly (r = 0.87 and 0.96, P < 0.001) correlated with each other in both the microsomal and mitochondrial fractions of Japanese livers. Subsequent results were obtained from in vitro experiments using liver microsomes based upon these findings. The oxidative deaminase activities of RIZ were inhibited completely by the nanomolar-order concentration of clorgyline and Ro 41-1049 (MAO-A selective inhibitors), but not by that of Ro 16-6491 (MAO-B selective inhibitor). The majority of the mean Michaelis-Menten values for three substrates toward MAO obtained from six Japanese and six Caucasian liver microsomes reached no significant differences between the two ethnic groups. The mean microsomal oxidative deaminase activities assessed in 18 Japanese and 20 Caucasian livers using the three substrates also showed no significant differences between the two ethnic groups. CONCLUSIONS: RIZ is mainly metabolized by MAO-A and the in vitro oxidative deaminase activities mediated via MAO-A and -B do not appear to differ between Japanese and Caucasians.     

Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro

This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity.     

Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo

Recent clinical evidence indicates that the broad spectrum anticonvulsant drug lamotrigine is effective against the depressive phase of bipolar illness and the difficult to treat rapid cycling form of the disorder. However, the molecular mechanism underlying this therapeutic action remains uncertain. Given that inhibition of the A-type of monoamine oxidase (MAO) is a proven antidepressant mechanism, we investigated the effects of lamotrigine on MAO activities in vitro and on monoamine disposition in vivo. In vitro, lamotrigine inhibited rat brain MAO activities with Ki values (MAO-A, 15 microM; MAO-B, 18 microM) potentially within the therapeutic range for this drug. The effects of lamotrigine on the MAO-A activities of rat brain and human liver preparations were almost identical suggesting minimal species or tissue variation. In contrast, there was no (MAO-A) or minimal (MAO-B) reduction in brain MAO activities when assayed ex vivo following the administration of lamotrigine to rats. In vivo brain microdialysis failed to detect meaningful alterations in extracellular hippocampal or frontal cortex monoamine concentrations. Furthermore, lamotrigine did not modulate oral tyramine-induced hypertension in rats or 5-hydroxytryptophan-induced head shaking in mice, providing strong evidence that the drug does not perturb monoamine metabolism in vivo. The absence of observable effects of lamotrigine on monoamine disposition in vivo may be explained by the competitive and highly reversible nature of the interaction of lamotrigine with MAO isoforms. Thus, altered monoamine metabolism in vivo is unlikely to account for the antidepressant action of the drug in bipolar depression.     

Isolation and characterization of a monoamine oxidase inhibitor from tobacco leaves

Recent positron emission tomography imaging studies have demonstrated a significant decrease in both monoamine oxidase A and B (MAO-A and MAO-B) activities in the brains of smokers. Normal levels of activity are observed in former smokers, suggesting the presence of one or more compounds in tobacco smoke that may inhibit these enzymes. In this paper, we report the results of efforts to identify compounds present in flue-cured tobacco leaves that inhibit MAO. The isolation procedure was guided by estimating the inhibitory properties of tobacco leaf extracts on the liver mitochondrial MAO-B-catalyzed oxidation of 1-methyl-4-(1-methylpyrrol-2-yl)-1,2,3, 6-tetrahydropyridine to the corresponding dihydropyridinium metabolite. Fractionation of extracts from flue-cured tobacco leaves led to the isolation of a competitive inhibitor of human MAO-A (K(i) = 3 microM) and MAO-B (K(i) = 6 microM), the structure of which could be assigned by classical spectroscopic analysis and confirmed by synthesis. This information may help to provide insights into some aspects of the pharmacology and toxicology of tobacco products.     

Monoamine oxidase inhibitory effects of pentanthrene type heterocyclic compounds]

Pentanthrene type heterocyclic compounds, which contain oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole or pyrrole ring as C-ring, and naphthalene, quinoline, isoquinoline or quinoxaline ring as A.B-ring, were prepared, and their monoamine oxidase (MAO) inhibitory activities were examined. As expected from our previous investigation on the structure-activity relationship of this series, most of them showed strong inhibitory potency to both MAO-A and MAO-B. However, a few indicated highly selective inhibition for either of MAO subtypes.     

Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase.

A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3-100 microM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease beta-amyloid deposition.     

Inhibition of Rat Platelet 5‐Hydroxytryptamine Uptake by Chlorpyrifos and Carbaryl

Abstract: The organophosphate insecticide chlorpyrifos and the carbamate insecticide carbaryl were investigated in adult male rats in terms of their effects on the activity of brain monoamine oxidase–A (MAO‐A) activity and on the platelet uptake of 5‐hydroxytryptamine (5‐HT). The activities of brain acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) were also determined. For each compound two different dosage regimens were employed. In the acute study, chlorpyrifos or carbaryl was administered at a single intraperitoneal dose of 100 mg/kg or 50 mg/kg, respectively. In the subacute study, chlorpyrifos was injected at a daily dose of 20 mg/kg for 7 days, while carbaryl was given at a daily dose of 10 mg/kg for 14 days. Acute chlorpyrifos administration produced a 85.01% inhibition of AChE and a 43.4% inhibition of BuChE but had no effect on MAO‐A activity and 5‐HT uptake. In contrast, subacute chlorpyrifos exposure caused a 94.96% inhibition of AChE and a 85.8% inhibition of BuChE and, also, elicited a significant (35.02%) reduction in the platelet uptake of 5‐HT. MAO‐A activity was not affected. Acute carbaryl administration produced a 56.38% AChE inhibition and a 55.95% BuChE inhibition and also caused a significant (26.36%) decrease in 5‐HT uptake but no change in MAO‐A. Subacute carbaryl exposure failed to affect significantly any of the biochemical parameters determined. Interference with the 5‐HT system by chlorpyrifos and carbaryl could contribute to the toxicity of these pesticides.     

Aliphatic propargylamines: potent, selective, irreversible monoamine oxidase B inhibitors.

A series of aliphatic propargylamine derivatives has been synthesized. Some of them possess highly potent, irreversible, selective, inhibitory activity toward monoamine oxidase B (MAO-B). The potency of the inhibitors is related to chain length and substitution of a hydrogen on the terminal carbon of the aliphatic chain. MAO inhibitory activity as assessed in vitro increased as the aliphatic carbon chain length increased. Substitution of a hydrogen by hydroxyl, carboxyl, or carbethoxyl groups at the aliphatic chain terminal or replacement of the methyl group on the nitrogen atom by an ethyl group considerably reduced the inhibitory activity. Stereospecific effects were observed with the R-(-)-enantiomer being 20-fold more active than the S-(+)-enantiomer. Inhibitors with relatively short carbon chain lengths (i.e. four to six carbons) were found to be more potent than those with longer chains in inhibiting brain MAO-B activity in vivo especially after oral administration. Chronic administration of low doses of the aliphatic propargylamines caused a slight cumulative inhibition of MAO-A activity in the mouse brain. These MAO-B inhibitors appear to be nontoxic, and they do not possess an amphetamine-like moiety in their structure as is the case for deprenyl. We expect that these aliphatic propargylamines may be useful in the treatment in certain neuropsychiatric disorders.     

Interaction of psychotropic drugs with monoamine oxidase in rat brain

Literature observations indicate that some psychotropic drugs may have inhibitory activity towards monoamine oxidase (MAO). This study was undertaken to assess the potency, isozyme selectivity and mechanism of inhibition of representative first- and second-generation antidepressant drugs towards rat brain MAO-A and MAO-B. Five tricyclic antidepressants (imipramine, trimipramine, clomipramine, amitriptyline and doxepine) and three selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine and citalopram) were examined. They showed inhibitory activity towards MAO-A and MAO-B, with clear selectivity for MAO-B (Ki in the micromolar range). Their mechanism of inhibition was competitive towards MAO-B and of a mixed competitive type towards MAO-A. The results suggest that some of the drugs examined might also contribute an MAO inhibitory effect in chronically treated patients.     

Synthesis of β‐amino acid derivatives and their inhibitory profiles against some metabolic enzymes

Sulfamate and its derivatives have a range of biological activities. One‐pot cyclocondensation of alkenes ( 1a–i ) with chlorosulfonyl isocyanate generates β‐lactams. β‐Amino acid derivatives ( 2a–i ) from β‐lactams were synthesized. Then, these highly reactive compounds were opened with MeOH to produce the corresponding sulfamate derivatives in good yields. The inhibitory effects of the novel sulfamate derivatives were tested on human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α‐glycosidase (α‐Gly). Novel sulfamate derivatives showed K_i values in the range of 23.81–42.97 nM against hCA I, 8.95–52.23 nM against hCA II, 8.10–45.51 nM against AChE, 23.16–81.84 nM against BChE, and 14.02–48.68 nM against α‐Gly. As a result, the novel sulfamate derivatives had potent inhibitory effects against both isoenzymes. Overall, due to the inhibitory effects of the novel sulfamate derivatives on the tested metabolic enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, epilepsy, leukemia, Alzheimer's disease, and type 2 diabetes mellitus, which are associated with high enzymatic activity of the indicated metabolic enzymes.     

Synthesis, biological evaluation and 3D-QSAR of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase A inhibitors

The present report provides a extended study of the chemistry, the inhibitory activity against monoamino oxidases (MAO), and molecular modeling including the 3D-QSAR hypothesis of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives. Four series of about eighty novel pyrazoline derivatives were prepared and investigated for their ability to inhibit the activity of the A and B isoforms of MAO selectively. Most of the new synthesized compounds proved more reversible, potent, and selective inhibitors of MAO-A than of MAO-B, and could be taken into account to develop the search further in this field, knowing that reversible and selective MAO-A inhibitors are used as antidepressant and antianxiety drug. The 30 most active compounds show inhibitory activity on MAO-A in the 8.6 x 10(-8) - 9.0 x 10(-9)M range. Moreover, it should be pointed out that for most of them a high IC(50) > or = 10(-9)M value is associated with a high A-selectivity (Selectivity Index MAO-B/MAO-A in the 10,000-16,250 range). Furthermore, due to the presence of a chiral centre at the C5 position of the pyrazole moiety, we performed the semi-preparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation, and from the results of these experiments it has been possible to point out a difference in inhibiting the two isoforms selectively between the racemic mixture and the single enantiomers. The molecular modeling work was carried out combining the Glide docking approach with CoMFA with the aim to rationalize the structure-activity relationships of each pyrazoline inhibitor toward MAO-A and MAO-B isoforms and to derive a suitable selectivity model.     

Protective effect of physostigmine and neostigmine against acute toxicity of parathion in rats

The effects of physostigmine and neostigmine on the parathin induced toxicity were examined in adult female rats. Physostigmine (100 μg/kg, ip) or neostigmine (200 μg/kg, ip) inhibited acetylcholinesterase (AChE) and cholinesterase (ChE) activities in blood, brain and lung when the enzyme activity was measured 30 min after the treatment. At the doses of two carbamates equipotent on brain AChE, neostigmine showed greater inhibition on peripheral AChE/ChE. The enzyme activity returned to normal in 120 min following the carbamates except in the lung of rats treated with neostigmine. Carbamates administered 30 min prior to parathion (2 mg/kg) antagonized the inhibition of AChE/ChE by parathion when the enzyme activity was measured 2 hr following parathion. Neostigmine showed greater protective effect on peripheral AChE/ChE. The effect of either carbamate on AChE/ChE was not significant 2 hr beyond the parathion treatment. Carbamates decreased the mortality of rats challenged with a lethal dose of parathion (4 mg/kg, ip) either when treated alone or in combination with atropine (10 mg/kg, ip). Lethal action of paraoxon (1.5 mg/kg, ip), the active metabolite of parathion, was also decreased by the carbamate treatment indicating that the protection was not mediated by competitive inhibition of metabolic conversion of parathion to paraoxon. The results suggest that carbamylation of the active sites may not be the sole underlying mechanism of protection provided by the carbamates.     

Selective inhibition by amiflamine of monoamine oxidase type A in rat brain,liver and duodenum

Summary Amiflamine (FLA 336(+)), N-desmethylamiflamine (FLA 788(+)) and N,N-didesmethylamiflamine (FLA 668(+)) were examined for their monoamine oxidase (MAO) inhibitory effects in rat brain, liver and duodenum and were compared with the irreversible inhibitors clorgyline and (-)-deprenyl. The potency of each FLA compound was the same in each tissue both in vitro and after oral administration with either serotonin or tyramine as substrate. The in vitro effect of FLA 788(+) was 2–6 times stronger than that of amiflamine although the compounds were equipotent after oral administration. FLA 668(+) was 2–3 times less potent than amiflamine in vitro and had very poor activity after oral administration. The deamination of phenethylamine was weakly afected by the three FLA compounds. Clorgyline inhibited strongly the deamination of serotonin and tyramine in the duodenum after oral administration, being 1,000 times more potent than in the brain and the liver. Similar results were obtained for (-)-deprenyl which, however, was more potent in inhibiting the deamination of phenethylamine than that of serotonin and tyramine. Amiflamine was a reversible MAO inhibitor with no MAO inhibitory capacity 24 h after a single oral dose. On the other hand the irreversible inhibitor clorgyline had a maximal effect on brain MAO 48 h after a single dose while the inhibitory effect in the duodenum had almost disappeared. The influence of amiflamine on the excretion of acid and basic metabolites of orally administered ¹⁴C-tyramine (58 mol/kg) in rat was examined. Amiflamine, at doses that strongly inhibited MAO-A in rat brain, only slightly affected the excretion of ¹⁴C-labelled acid in urine during 6 and 24 h after the tyramine administration. The results in this study suggest that other factors than a low interaction with intestinal MAO may be of importance for the low tyramine potentiating effect obtained after oral administration of amiflamine.     

Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)- pyrazole derivatives

A novel series of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazole derivatives have been synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). All the synthesized compounds show high activity against both the MAO-A and the MAO-B isoforms with Ki values between 27 and 4 nM and between 50 and 1.5 nM, respectively, except for a few derivatives whose inhibitory activity against MAO-B was in the micromolar range. Knowing that stereochemistry may be an important modulator of biological activity, we performed the semipreparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation. The selectivity of the (-)-(S)-1 enantiomer against MAO-B increases twice and a half, while the selectivity of the (-)-(S)-4 enantiomer against MAO-A triples. Both the MAO-A and MAO-B isoforms respectively of the 1O5W and 1GOS models deposited in the Protein Data Bank were considered in the computational study. The docking study was carried out using several computational approaches with the aim of proposing possible binding modes of the MAO enantioselective compounds 1 and 4.