E. Fernández-Alvarez

Relevance of benzyloxy group in 2-indolyl methylamines in the selective MAO-B inhibition.

Previous studies with indolyl derivatives as monoamine oxidase (MAO) inhibitors have shown the relevance of the indole structure for recognition by the active site of this enzyme. We now report a new series of molecules with structural features which determine the selectivity of MAO inhibition. A benzyloxy group attached at position 5 of the indole ring is critical for this selective behaviour. Amongst all of these benzyloxy‐indolyl methylamines, N‐(2‐propynyl)‐2‐(5‐benzyloxyindol)methylamine FA‐73 was the most potent MAO‐B ‘suicide’ inhibitor studied. The Ki values for MAO‐A and MAO‐B were 800±60 and 0.75±0.15 nM, respectively. These data represent a selectivity value of 1066 for MAO‐B, being 48 times more selective than L‐deprenyl (Ki values of 376±0.032 and 16.8±0.1 nM for MAO A and MAO‐B, respectively). The IC50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150±8 μM for FA‐73 and 68±10 μM for L‐deprenyl whereas in human caudate tissue the IC50 values were 0.36±0.015 μM for FA‐73 and 0.10±0.007 μM for L‐deprenyl. Moreover, mouse brain MAO‐B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg−1 adminstration, MAO‐A activity was not affected. These novel molecules should provide a better understanding of the active site of monoamine oxidase and could be the starting point for the design of further selective, non‐amphetamine‐like MAO‐B inhibitors with therapeutic potential for the treatment of neurological disorders.

2-Arylamino-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidines: synthesis and diuretic activity

Abstract The synthesis of a series of 19 new compounds, 2-arylamino-4-oxo-3,4-dihydropyrido[2,3- d ]pyrimidines 9 , and the results of a study of their potassium-sparing diuretic activity are reported. Compounds 9 were obtained by boiling in dimethylformamide a solution of 2-methylthio-4-oxo-3,4-dihydropyrido[2,3- d ]pyrimidine hydrochloride ( 5 HCl, method A) or 2-chloro-4-oxo-3,4-dihydropyrido[2,3- d ]pyrimidine hydrochloride ( 8 HCl, method B) and the respective substituted aniline. Some of the compounds showed significant diuretic and potassium-sparing activities. Quantitative structure—activity relationships are described.

New 5H-1,2,4-triazino[5,6-b]indole and aminoindole derivatives. Synthesis and studies as inhibitors of blood platelet aggregation, anti-hypertensive agents and thromboxane synthetase inhibitors

Abstract This paper reports the synthesis of a series of 5H-1,2,4-triazino[5,6-b]indole 3 and 4, and aminoindole 12–23, derivatives, obtained from isatin 1 and from oxoindole 5, respectively. All the new compounds were studied as antihypertensive agents in spontaneously hypertensive rats (SHR), and as inhibitors of platelet aggregation in guinea pig whole blood, induced by arachidonic acid (AA), adenosin-5′-diphosphate (ADP) or collagen. The most active antiaggregating compounds were also studied as thromboxane A2 synthetase inhibitors.

Synthesis of asymmetric 1-amino-2-phenylcyclopropanecarboxylic acids by diastereoselective cyclopropanation of highly functionalized homochiral olefines

Abstract Homochiral benzylidenediketopiperazine and α-benzoylaminocinnamic esters react with diazomethane giving high to good diastereomeric ratios of spiropyrazoline derivatives which, on photolysis and acid hydrolysis of the resulting spirocyclopropyl compounds gave, respectively, (+)- and (−)-1-amino-2-phenylcyclopropanecarboxylic acids.

Acetylenic and allenic derivatives of 2-(5-benzyloxyindolyl) and 2-(5-hydroxyindolyl)methylamines: synthesis and in vitro evaluation as monoamine oxidase inhibitors

Abstract We report the synthesis and in vitro studies as MAO inhibitors of 2 series of new acetylenic and allenic derivatives of 2-(5-benzyloxyindolyl)- and 2-(5-hydroxyindolyl)methylamines and their indolylmethylamine precursors. All compounds were MAO inhibitors and either did not show selectivity (the benzyloxy compounds 5 ) or were selective for MAO-A (most of the hydroxy compounds 7 ). Three of the studied compounds, 7d , 7g and 7i , were found to be slightly more selective for MAO-A than clorgyline.

Enantioselective synthesis of (+)-(1R,2S)-allocoronamic acid

Abstract The asymmetric synthesis of (+)-(1R,2S)-allocoronamic acid is reported. Diazomethane addition to (Z)-N-( tert -butoxycarbonyl)ethyldehydroalanyl-L-prolin-anhydride, easily prepared from (Z)-2-phenyl-4-propylidene-5(4H)-oxazolone and L-proline, gave in high diastereomeric excess the corresponding spiropyrazoline, which was transformed, on photolysis and acid hydrolysis of the resulting spirocyclopropane, into (+)-(1R,2S)-1-amino-2-ethyl-cyclopropanecarboxylic acid.

The effect of side chain substitution at positions 2 and 3 of the heterocyclic ring of N-acetylenic analogues of tryptamine as monoamine oxidase inhibitors

N-Acetylenic analogues of tryptamine in which the side chain is located at position 2 of the indole ring are compared with those in which the side chain is located at position 3, in terms of their actions as inhibitors of monoamine oxidases A and B. IC50 values at 0 and 30 min of pre-incubation were determined. Time-dependence and irreversible inhibition confirmed that all of them behave as mechanism-based inhibitors. The kinetic constants of each inhibition step were determined for both monoamine oxidase forms and compared between them. In all cases the first-order rate constants for the covalent adduct formation were similar to inhibitor selectivity which is derived solely from differences in affinities for non-covalent binding to the A and B enzymes. Those compounds where the acetylenic side chain was substituted at position 2 of the heterocyclic ring and selective inhibitors of monoamine oxidase A were more potent than those with the side chain in position 3.

The kinetics of monoamine oxidase inhibition by three 2-indolylmethylamine derivatives

The inhibition of bovine brain mitochondrial MAO-A and MAO-B by three acetylenic and non-acetylenic derivatives of 2-indolylmethylamine, chosen among more than 100 new compounds, were studied. The non-acetylenic derivative N-methyl-2(5-hydroxy-1-methylindolyl)methylamine (1) was a weak non-selective inhibitor which was shown to act in a reversible and competitive manner towards the deamination of tyramine. The two acetylenic derivatives N-methyl-N-(2-propynyl)-2-(5-benzyloxy-1-methylindolyl)methylamine (2) and N-methyl-N-(2-propynyl)-2-(5-hydroxy-1-methylindolyl)methylamine (3) were potent MAO inhibitors, one of them non-selective (compound 2) and the other MAO-A selective inhibitor (compound 3). Both of them were irreversible and competitive inhibitors, compound 2 towards the deamination of tyramine and compound 3 towards the deamination of serotonin and beta-phenylethylamine. A mechanism for the inhibition of the enzyme by both irreversible inhibitors is proposed and the inhibition parameters are determined.

Inhibition of catechol-O-methyltransferase by 1-vinyl derivatives of nitrocatechols and nitroguaiacols: Kinetics of the irreversible inhibition by 3-(3-hydroxy-4-methoxy-5-nitro benzylidene)-2,4-pentanedione

It is well known that activated alkene derivatives react with thiol groups according to a Michaels addition reaction. On the basis of the presence of at least one thiol group essential for the activity of catechol-O-methyltransferase (COMT), several 1-vinyl derivatives of nitrocatechol and nitroguaiacol were synthesized and tested as potential irreversible active site-directed inhibitors of COMT. All the synthesized products were potent inhibitors of partially purified pig liver COMT. However, the inhibition was reversible in most cases, with the exception of 3-(3-hydroxy-4-methoxy-5-nitrobenzylidene)-2,4-pentanedione (compound 2) which inhibited COMT in an irreversible manner. When the inhibition of COMT was measured as a function of the length of time of pre-incubation with 2, biphasic kinetics were observed, suggesting the modification of at least two thiol groups which are essential for COMT activity. The analysis of the two parts of the inhibition curve as a function of the inhibitor concentration showed that compound 2 modified the more reactive group in a non-specific manner, while it behaved as an active site-directed inhibitor on the second slow-reacting thiol group. Importantly, a saturating concentration of S-adenosyl-L-methionine (AdoMet) in the pre-incubation mixture gave pseudo-first order kinetics, suggesting total protection of one thiol group. Magnesium ions had no effect on the protection of COMT by AdoMet. In the presence of 3,5-dinitrocatechol (DNC) slight protection of COMT was observed; when the inactivation of both groups was analysed independently, protection of the specifically modified group was detected, while the reaction with the other group was faster in the presence of DNC. When both AdoMet and DNC were present, inactivation of COMT by 2 was not observed, suggesting that both reacting groups are located at or near the active site.

Synthesis of asymmetric (E)-α-(2-phenylcyclopropyl)glycines

Abstract An asymmetric synthesis of (E)-α-(2-phenylcyclopropyl)glycines is reported. The key step is the dibromocyclopropanation of tert-Butyl (E,4R) or (E,4S)-2,2-dimethyl-4-(2′-phenylvinyl)-3-oxazolidinecarboxylates, easily prepared from L or D-serine, respectively. This reaction gives good diastereomeric ratios of dibromocyclopropanes. The major compounds were transformed, in three steps, in the corresponding cyclopropylaminoacids.