Discovery of two new classes of potent monoamine oxidase-B inhibitors by tricky chemistry (original) (raw)
Related papers
Chromone, a Privileged Scaffold for the Development of Monoamine Oxidase Inhibitors
Journal of Medicinal Chemistry, 2011
Two series of novel chromone derivatives were synthesized and investigated for their ability to inhibit the activity of monoamine oxidase. The SAR data indicate that chromone derivatives with substituents in position 3 of γ-pyrone nucleus act preferably as MAO-B inhibitors, with IC 50 values in the nanomolar to micromolar range. Almost all chromone 3-carboxamides display selectivity toward MAO-B. Identical substitutions on position 2 of γpyrone nucleus result in complete loss of activity in both isoforms (chromones 2À12 except 3 and 5). Notably, chromone (19) exhibits an MAO-B IC 50 of 63 nM, greater than 1000-fold selectivity over MAO-A, and behaves as a quasi-reversible inhibitor. Docking experiments onto the MAO binding of the most active compound highlight different interaction patterns among the isoforms A and B. The differential analysis of the solvation effects among the chromone isomers gave additional insight about the superior outline of the 3-substituted chromone derivatives.
Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors
Bioorganic & Medicinal Chemistry, 2011
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 b-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of b-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.
Acta Crystallographica Section E Crystallographic Communications, 2015
SixN-substituted-phenyl 4-oxo-4H-chromene-3-carboxamides, namelyN-(2-nitrophenyl)-4-oxo-4H-chromene-3-carboxamide, C16H10N2O5(2b),N-(3-methoxyphenyl)-4-oxo-4H-chromene-3-carboxamide, C17H13NO4, (3a),N-(3-bromophenyl)-4-oxo-4H-chromene-3-carboxamide, C16H10BrNO3, (3b),N-(4-methoxyphenyl)-4-oxo-4H-chromene-3-carboxamide, C17H13NO4, (4a),N-(4-methylphenyl)-4-oxo-4H-chromene-3-carboxamide, C17H13NO3, (4d), andN-(4-hydroxyphenyl)-4-oxo-4H-chromene-3-carboxamide, C16H11NO4, (4e), have been structurally characterized. All compounds exhibit ananticonformation with respect to the C—N rotamer of the amide and atrans-related conformation with the carbonyl groups of the chromone ring of the amide. These structures present an intramolecular hydrogen-bonded network comprising an N—H...O hydrogen bond between the amide N atom and the O atom of the carbonyl group of the pyrone ring, forming anS(6) ring, and a weak Car—H...O hydrogen bond in which the carbonyl group of the amide acts as acceptor for...
Synthesis and evaluation of chromone derivatives as inhibitors of monoamine oxidase
Molecular Diversity, 2019
Based on reports that chromone compounds are good potency inhibitors of monoamine oxidase (MAO), the present study evaluates the effect of substitution with flexible side chains on the 3 position on MAO inhibition potency. Fifteen chromone derivatives were synthesised by reacting aromatic and aliphatic amines and alcohols with chromone 3-carboxylic acid in the presence of carbonyldiimidazole (CDI). This yielded chromane-2,4-dione and ester chromone derivatives. Generally, the esters exhibited weak MAO inhibition, while the chromane-2,4-dione derivatives showed promise as selective MAO-B inhibitors with IC 50 values in the micromolar range. Compound 14b, 3-[(benzylamino)methylidene]-3,4-dihydro-2H-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC 50 value of 638 µM. This compound was shown to be a reversible and competitive MAO-B inhibitor with a K i of 94 µM. In conclusion, the effect of chain elongation and introduction of flexible substituents on position 3 of chromone were explored and the results showed that aminomethylidene substitution is preferable over ester substitution. Good potency MAO-B inhibitors may act as leads for the design and development of therapy for Parkinson's disease where these agents reduce the central metabolism of dopamine.
2‐Phenyloxazole‐4‐carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B
ChemMedChem, 2019
A series of 2-phenyloxazole-4-carboxamides (4a-o) behaving as competitive inhibitors of human monoamine oxidases (MAOs) with good selectivity toward the MAO-B isoform is described. Some derivatives were also able to inhibit MAO activity in NGFdifferentiated PC12 cells, taken as a cellular model. In particular, derivative 4a exerts the highest inhibitory effect without compromising cell viability. Molecular docking analysis allowed rationalizing the experimentally observed binding affinity and selectivity.
Inhibition of monoamine oxidase by selected C6-substituted chromone derivatives
European Journal of Medicinal Chemistry, 2012
Chromone has been reported to be a useful scaffold for the design of monoamine oxidase (MAO) inhibitors. In an attempt to discover highly potent MAO inhibitors and to contribute to the known structureeactivity relationships (SAR) of MAO inhibition by chromones, in the present study, we have synthesized a series of chromone derivatives substituted at C6 with a variety of alkyloxy substituents, and evaluated the resulting compounds as inhibitors of recombinant human MAO-A and-B. The results document that the C6-substituted chromones are potent reversible MAO-B inhibitors with IC 50 values in the low nM range (2e76 nM). The chromones were also found to bind reversibly to MAO-A, but with lower affinities compared to MAO-B. It may therefore be concluded that C6-substituted chromones are highly potent MAO-B selective inhibitors and promising lead compounds for the development of therapy for neurodegenerative disorders such as Parkinson's disease. The results of this study are discussed with reference to possible binding orientations of a selected C6-substituted chromone in the active site cavities of MAO-A and-B.
Molecules, 2016
The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer's disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC 50 = 8.99 µM) and a potent and selective MAO-B inhibitor (IC 50 = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 µM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepam.
European Journal of Medicinal Chemistry, 46, 4665-4668, 2011. , 2011
The synthesis, biological evaluation and molecular modeling of new multipotent inhibitors of type I and type II, able to simultaneously inhibit monoamine oxidases (MAO) as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), is described. Compounds of type I were prepared by sequential reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (14) [or 2,6-dichloropyridine-3,5-dicarbonitrile (15)] with prop-2-yn-1-amine (or N-methylprop-2-yn-1-amine) and 2-(1-benzyl-piperidin-4-yl)alkylamines 22–25. Compounds of type II were prepared by Friedländer type reaction of 6-amino-5-formyl-2-(methyl(prop-2-yn-1-yl)amino)nicotinonitriles 32 and 33 with 4-(1-benzylpiperidin-4-yl)butan-2-one (31). The biological evaluation of molecules 1–11 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO-A and MAO-B inhibition. Kinetic studies of compound 8 proved that this is a EeAChE mixed type inhibitor (IC50 = 16 ± 2; Ki = 12 ± 3 nM). Molecular modeling investigation on compound 8 confirmed its dual AChE inhibitory profile, binding simultaneously at the catalytic active site (CAS) and at the peripheric anionic site (PAS). In overall, compound 11, as a potent and selective dual AChEI, showing a moderate and selective MAO-A inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer’s disease.► The syntheses of compounds 1–11, hybrids from donepezil and PF9601N are reported. ► N-benzyl piperidine and propargylamine moieties target AChE and MAO, respectively. ► Multipotent compound 11 displays selective AChE and MAO-A inhibitory profile. ► Kinetic studies proved compound 8 is a EeAChE mixed type inhibitor. ► The length of the spacer is the most sensitive moiety to modulate AChE inhibition.
(E)-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors
European Journal of Medicinal Chemistry, 2016
A series of (E)-3-heteroarylidenechroman-4-ones (1a-r) was designed, synthesized and investigated in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO) isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors showing IC 50 values in the nanomolar or micromolar range. (E)-5,7-Dichloro-3-{[(2-(dimethylamino)pyrimidin-5-yl]methylene}chroman-4-one (1c) was the most interesting compound identified in this study, endowed with higher hMAO-B potency (IC 50 = 10.58 nM) and selectivity (SI > 9452) with respect to the reference selective inhibitor selegiline (IC 50 = 19.60 nM, IC 50 > 3431). Molecular modeling studies were performed for rationalizing at molecular level the target selective inhibition of our compounds, revealing a remarkable contribution of hydrogen bond network and water solvent.