ABSTRACT
Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3-arylcoumarin derivatives were previously described as interesting selective MAO-B inhibitors. Preserving the trans-stilbene structure, a series of 2-arylbenzofuran and corresponding 3-arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO-A and MAO-B. In general, both types of derivatives were found to be selective MAO-B inhibitors, with IC50 values in the nano- to micromolar range. 5-Nitro-2-(4-methoxyphenyl)benzofuran (8) is the most active compound of the benzofuran series, presenting MAO-B selectivity and reversible inhibition (IC50 =140 nM). 3-(4'-Methoxyphenyl)-6-nitrocoumarin (15), with the same substitution pattern as that of compound 8, was found to be the most active MAO-B inhibitor of the coumarin series (IC50 =3 nM). However, 3-phenylcoumarin 14 showed activity in the same range (IC50 =6 nM), is reversible, and also severalfold more selective than compound 15. Docking experiments for the most active compounds into the MAO-B and MAO-A binding pockets highlighted different interactions between the derivative classes (2-arylbenzofurans and 3-arylcoumarins), and provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of these scaffolds.
Subject(s)
Benzofurans/pharmacology , Coumarins/pharmacology , Enzyme Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Benzofurans/chemical synthesis , Benzofurans/chemistry , Coumarins/chemical synthesis , Coumarins/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Series of 3-indolyl and 3-thiophenylcoumarins were synthesized and evaluated as inhibitors of the two human MAO isoforms, hMAO-A and hMAO-B. In general, the derivatives were found to be selective hMAO-B inhibitors with IC(50) values in the nanoMolar (nM) to microMolar (µM) range. Docking experiments were carried out in order to compare the theoretical and experimental affinity of these compounds to the hMAO-B protein. According to our results, docking experiments could be an interesting approach to try to predict the activity of this class of coumarins against MAO-B receptors.
Subject(s)
Coumarins/chemical synthesis , Coumarins/pharmacology , Models, Molecular , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Coumarins/chemistry , Coumarins/metabolism , Humans , Monoamine Oxidase/chemistry , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/metabolism , Protein ConformationABSTRACT
A series of 6-halo-3-hydroxyphenylcoumarins (resveratrol-coumarins hybrid derivatives) was synthesized in good yields by a Perkin reaction followed by hydrolysis. The new compounds were evaluated for their vasorelaxant activity in intact rat aorta rings pre-contracted with phenylephrine (PE), as well as for their inhibitory effects on platelet aggregation induced by thrombin in washed human platelets. These compounds concentration-dependently relaxed vascular smooth muscle and some of them showed a platelet antiaggregatory activity that was up to thirty times higher than that shown by trans-resveratrol and some other previously synthesized derivatives.
Subject(s)
Coumarins/chemical synthesis , Coumarins/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Vasodilator Agents/chemical synthesis , Vasodilator Agents/pharmacology , Animals , Chromonar/chemistry , Coumarins/chemistry , Female , Humans , In Vitro Techniques , Inhibitory Concentration 50 , Male , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemistry , Rats , Rats, Wistar , Resveratrol , Stilbenes/chemistry , Vasodilation/drug effects , Vasodilator Agents/chemistry , Warfarin/chemistryABSTRACT
A series of 6-methyl-3-phenylcoumarins 3-6 were synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. A comparative study between the three possible mono methoxy 3-phenyl derivatives and the p-hydroxy analogue is reported. The synthesis of these new resveratrol-coumarin hybrids was carried out by a Perkin reaction between the 5-methylsalicylaldehyde and the corresponding phenylacetic acids. The p-methoxy substituted compound 3 was hydrolyzed to 6 by a traditional reaction with hydriodic acid. The prepared compounds show high selectivity to the MAO-B isoenzyme, some of them with IC(50) values in the low nanomolar range. Compound 4, with the methoxy group in meta position, is the most active of this series, with an IC(50) against MAO-B of 0.80 nM, and is several times more potent and MAO-B selective than the R-(-)-deprenyl (reference compound).
Subject(s)
Coumarins/chemical synthesis , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase/chemistry , Coumarins/chemistry , Coumarins/pharmacology , Humans , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Parkinson Disease/drug therapy , Protein Isoforms/chemistry , Protein Isoforms/metabolismABSTRACT
In the present work we report on the contribution of the coumarin moiety to tyrosinase inhibition. Coumarin-resveratrol hybrids 1-8 have been resynthesized to investigate the structure-activity relationships and the IC(50) values of these compounds were measured. The results showed that these compounds exhibited tyrosinase inhibitory activity. Compound 3-(3',4',5'-trihydroxyphenyl)-6,8-dihydroxycoumarin (8)is the most potentcompound (0.27 mM), more so than umbelliferone (0.42 mM), used as reference compound. The kinetic studies revealed that compound 8 caused non-competitive tyrosinase inhibition.
Subject(s)
Coumarins/pharmacology , Enzyme Inhibitors/pharmacology , Monophenol Monooxygenase/antagonists & inhibitors , Stilbenes/pharmacology , Coumarins/chemistry , Inhibitory Concentration 50 , Resveratrol , Stilbenes/chemistry , Structure-Activity RelationshipABSTRACT
6-Methyl-3-phenylcoumarins 3-6 were designed, synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. The synthesis of these new compounds (resveratrol-coumarin hybrids) was carried out with good yield by a Perkin reaction, from the 5-methylsalicylaldehyde and the corresponding phenylacetic acid. They show high selectivity to the MAO-B isoenzyme, with IC(50) values in the nanomolar range. Compound 5 is the most active compound and is several times more potent and selective than the reference compound, R-(-)-deprenyl.
Subject(s)
Coumarins/chemistry , Coumarins/pharmacology , Monoamine Oxidase Inhibitors/chemistry , Stilbenes/chemistry , Antioxidants , Coumarins/chemical synthesis , Drug Design , Humans , Inhibitory Concentration 50 , Monoamine Oxidase/drug effects , Monoamine Oxidase Inhibitors/chemical synthesis , Resveratrol , Selegiline/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis of four pyranocoumarins starting from phloroglucinol and the complete (1)H and (13)C NMR assignment of seven pyranocoumarins has been performed using 1D and 2D NMR techniques including COSY, HMQC and HMBC experiments.
Subject(s)
Magnetic Resonance Spectroscopy , Phloroglucinol/chemical synthesis , Pyranocoumarins/chemical synthesis , Carbon Isotopes , Molecular Structure , Phloroglucinol/chemistry , Protons , Pyranocoumarins/chemistryABSTRACT
The mass spectrometric behaviour of a series of 6,6-disubstituted dibenzo(d,f)(1,3)dioxepine derivatives have been studied. The fragmentation patterns were described and discussed in detail with the aid of labelled compounds, accurate mass measurements and collisionally induced dissociation experiments performed using an ion trap.
