Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Mol Divers ; 25(2): 753-762, 2021 May.
Article in English | MEDLINE | ID: mdl-32108308

ABSTRACT

The most effective treatment of Parkinson's disease is restoring central dopamine levels with levodopa, the metabolic precursor of dopamine. However, due to extensive peripheral metabolism by aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT), only a fraction of the levodopa dose reaches the brain unchanged. Thus, by preventing levodopa metabolism and increasing the availability of levodopa for uptake into the brain, the inhibition of COMT would be beneficial in Parkinson's disease. Although nitrocatechol COMT inhibitors have been used in the treatment of Parkinson's disease, efforts have been made to discover non-nitrocatechol inhibitors. In the present study, the 3-hydroxypyridin-4-one scaffold was selected for the design and synthesis of non-nitrocatechol COMT inhibitors since the COMT inhibitory potential of this class has been illustrated. Using COMT obtained from porcine liver, it was shown that a synthetic series of ten 3-hydroxypyridin-4-ones are in vitro inhibitors with IC50 values ranging from 4.55 to 19.8 µM. Although these compounds are not highly potent inhibitors, they may act as leads for the development of non-nitrocatechol COMT inhibitors. Such compounds would be appropriate for the treatment of Parkinson's disease. 3-Hydroxypyridin-4-ones have been synthesised and evaluated as non-nitrocatechol COMT inhibitors. In vitro, the IC50 values ranged from 4.55 to 19.8 µM.


Subject(s)
Catechol O-Methyltransferase Inhibitors , Pyridines , Animals , Catechol O-Methyltransferase/chemistry , Catechol O-Methyltransferase Inhibitors/chemical synthesis , Catechol O-Methyltransferase Inhibitors/chemistry , Drug Design , Liver/enzymology , Models, Molecular , Pyridines/chemical synthesis , Pyridines/chemistry , Swine
2.
Mol Divers ; 23(4): 897-913, 2019 Nov.
Article in English | MEDLINE | ID: mdl-30666491

ABSTRACT

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 IC50 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 IC50 value of 638 µM. This compound was shown to be a reversible and competitive MAO-B inhibitor with a Ki 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.


Subject(s)
Chromones/chemical synthesis , Monoamine Oxidase Inhibitors/chemical synthesis , Chromones/chemistry , Monoamine Oxidase/chemistry , Monoamine Oxidase Inhibitors/chemistry , Recombinant Proteins/chemistry
3.
Org Biomol Chem ; 14(33): 7899-911, 2016 Aug 16.
Article in English | MEDLINE | ID: mdl-27477595

ABSTRACT

The design, synthesis and biological evaluation of a series of 6-aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines is described. These compounds exhibited in vitro antiplasmodial activity in the low nanomolar range against both drug sensitive and drug resistant strains of P. falciparum, with 1-(3-(2,4-dichlorophenoxy)propyl)-6-phenyl-1,6-dihydro-1,3,5-triazine-2,4-diamine hydrochloride identified as the most potent compound from this series against the drug resistant FCR-3 strain (IC50 2.66 nM). The compounds were not toxic to mammalian cells at therapeutic concentrations and were shown to be inhibitors of parasitic DHFR in a biochemical enzyme assay.


Subject(s)
Antimalarials/pharmacology , Diamines/pharmacology , Drug Design , Folic Acid Antagonists/pharmacology , Plasmodium falciparum/drug effects , Triazines/pharmacology , Antimalarials/chemical synthesis , Antimalarials/chemistry , Diamines/chemical synthesis , Diamines/chemistry , Dose-Response Relationship, Drug , Folic Acid Antagonists/chemical synthesis , Folic Acid Antagonists/chemistry , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistry
4.
Bioorg Med Chem Lett ; 26(3): 734-738, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26776359

ABSTRACT

A novel series of carbamate substituted 2-amino-4,6-diphenylpyrimidines was evaluated as potential dual adenosine A1 and A2A receptor antagonists. The majority of the synthesised compounds exhibited promising dual affinities, with A1Ki values ranging from 0.175 to 10.7 nM and A2AKi values ranging from 1.58 to 451 nM. The in vivo activity illustrated for 3-(2-amino-6-phenylpyrimidin-4-yl)phenyl morpholine-4-carboxylate (4c) is indicative of the potential of these compounds as therapeutic agents in the treatment of Parkinson's disease, although physicochemical properties may require optimisation.


Subject(s)
Adenosine A1 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/chemistry , Pyrimidines/chemistry , Binding Sites , Carbamates/chemistry , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Kinetics , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Pyrimidines/metabolism , Receptor, Adenosine A1/chemistry , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A2A/chemistry , Receptor, Adenosine A2A/metabolism , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 25(22): 5270-6, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26432037

ABSTRACT

Studies have shown that natural and synthetic chalcones (1,3-diphenyl-2-propen-1-ones) possess monoamine oxidase (MAO) inhibition activities. Of particular importance to the present study is a report that a series of furanochalcones acts as MAO-B selective inhibitors. Since the effect of heterocyclic substitution, other than furan (and more recently thiophene, piperidine and quinoline) on the MAO inhibitory properties of the chalcone scaffold remains unexplored, the aim of this study was to synthesise and evaluate further heterocyclic chalcone analogues as inhibitors of the human MAOs. For this purpose, heterocyclic chalcone analogues that incorporate pyrrole, 5-methylthiophene, 5-chlorothiophene and 6-methoxypyridine substitution were examined. Seven of the nine synthesised compounds exhibited IC50 values <1 µM for the inhibition of MAO-B, with all compounds exhibiting higher affinities for MAO-B compared to the MAO-A isoform. The most potent MAO-B inhibitor (4h) displays an IC50 value of 0.067 µM while the most potent MAO-A inhibitor (4e) exhibits an IC50 value of 3.81 µM. It was further established that selected heterocyclic chalcones are reversible and competitive MAO inhibitors. 4h, however, may exhibit tight-binding to MAO-B, a property linked to its thiophene moiety. We conclude that high potency chalcones such as 4h represent suitable leads for the development of MAO-B inhibitors for the treatment of Parkinson's disease and possibly other neurodegenerative disorders.


Subject(s)
Antiparkinson Agents/pharmacology , Chalcones/pharmacology , Hydrocarbons, Fluorinated/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Pyrroles/pharmacology , Thiophenes/pharmacology , Antiparkinson Agents/chemical synthesis , Antiparkinson Agents/toxicity , Chalcones/chemical synthesis , Chalcones/toxicity , HeLa Cells , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/toxicity , Kinetics , Kynuramine/metabolism , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/toxicity , Pyrroles/chemical synthesis , Pyrroles/toxicity , Structure-Activity Relationship , Thiophenes/chemical synthesis
6.
Eur J Med Chem ; 104: 177-88, 2015 Nov 02.
Article in English | MEDLINE | ID: mdl-26462195

ABSTRACT

In this study thirteen 2-aminopyrimidine derivatives were synthesised and screened as potential antagonists of adenosine A1 and A2A receptors in order to further investigate the structure activity relationships of this class of compounds. 4-(5-Methylfuran-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (8m) was identified as a compound with high affinities for both receptors, with an A2AKi value of 6.34 nM and an A1Ki value of 9.54 nM. The effect of selected compounds on the viability of cultured cells was assessed and preliminary results indicate low cytotoxicity. In vivo efficacy at A2A receptors was illustrated for compounds 8k and 8m since these compounds attenuated haloperidol-induced catalepsy in rats. A molecular docking study revealed that the interactions between the synthesised compounds and the adenosine A2A binding site most likely involve Phe168 and Asn253, interactions which are similar for structurally related adenosine A2A receptor antagonists.


Subject(s)
Adenosine A1 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/pharmacology , Pyrimidines/pharmacology , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A2A/metabolism , Adenosine A1 Receptor Antagonists/chemical synthesis , Adenosine A1 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Animals , Catalepsy/chemically induced , Catalepsy/prevention & control , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Haloperidol , HeLa Cells , Humans , Male , Molecular Docking Simulation , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
7.
Bioorg Chem ; 49: 49-58, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23892098

ABSTRACT

The adenosine A2A receptor is considered to be an important target for the development of new therapies for Parkinson's disease. Several antagonists of the A2A receptor have entered clinical trials for this purpose and many research groups have initiated programs to develop A2A receptor antagonists. Most A2A receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high affinity A2A receptor antagonists and to further explore the structure-activity relationships (SARs) of A2A antagonism by the xanthine class of compounds, this study examines the A2A antagonistic properties of series of (E)-8-styrylxanthines, 8-(phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines. The results document that among these series, the (E)-8-styrylxanthines have the highest binding affinities with the most potent homologue, (E)-1,3-diethyl-7-methyl-8-[(3-trifluoromethyl)styryl]xanthine, exhibiting a Ki value of 11.9 nM. This compound was also effective in reversing haloperidol-induced catalepsy in rats, providing evidence that it is in fact an A2A receptor antagonist. The importance of substitution at C8 with the styryl moiety was demonstrated by the finding that none of the 8-(phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines exhibited high binding affinities for the A2A receptor.


Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Enzyme Inhibitors/pharmacology , Receptor, Adenosine A2A/metabolism , Xanthines/pharmacology , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Monoamine Oxidase/metabolism , Recombinant Proteins/metabolism , Structure-Activity Relationship , Xanthines/chemical synthesis , Xanthines/chemistry
8.
Bioorg Med Chem Lett ; 23(17): 4985-9, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23860591

ABSTRACT

The validity of the chalcone scaffold for the design of inhibitors of monoamine oxidase has previously been illustrated. In a systematic attempt to investigate the effect of heterocyclic substitution on the monoamine oxidase inhibitory properties of this versatile scaffold, a series of furanochalcones were synthesized. The results demonstrate that these furan substituted phenylpropenones exhibited moderate to good inhibitory activities towards MAO-B, but showed weak or no inhibition of the MAO-A enzyme. The most active compound, 2E-3-(5-chlorofuran-2-yl)-1-(3-chlorophenyl)prop-2-en-1-one, exhibited an IC50 value of 0.174 µM for the inhibition of MAO-B and 28.6 µM for the inhibition of MAO-A. Interestingly, contrary to data previously reported for chalcones, these furan substituted derivatives acted as reversible inhibitors, while kinetic analysis revealed a competitive mode of binding.


Subject(s)
Chalcones/chemistry , Chalcones/pharmacology , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Furans/chemistry , Furans/pharmacology , Humans , Monoamine Oxidase/metabolism , Recombinant Proteins/metabolism
9.
Bioorg Med Chem Lett ; 22(24): 7367-70, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23122857

ABSTRACT

It has recently been reported that nitrile containing compounds frequently act as potent monoamine oxidase B (MAO-B) inhibitors. Modelling studies suggest that this high potency inhibition may rely, at least in part, on polar interactions between nitrile functional groups and polar moieties within the MAO-B substrate cavity. In an attempt to identify potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC(50) values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC(50)=0.025 µM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson's disease.


Subject(s)
Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Nitriles/pharmacology , Phthalic Acids/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Conformation , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Nitriles/chemical synthesis , Nitriles/chemistry , Phthalic Acids/chemical synthesis , Phthalic Acids/chemistry , Structure-Activity Relationship
10.
Eur J Med Chem ; 46(6): 2022-30, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21420762

ABSTRACT

A small set of novel 2,N6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines was prepared possessing a flexible tether between the exocyclic nitrogen bonded to C-6 of the 1,2-dihydro-1,3,5-triazine-4,6-diamine heterocycle and the distal aryl ring. Three zones were varied in this series of compounds, namely the nature of the substituent(s) on C-2; the nature of the substituent(s) on the distal aryl ring; as well as the nature and length of the flexible tether between the rings. The compound showing the best antimalarial activity (cycloguanil-resistant FCR-3 Plasmodium falciparum IC50=0.99 µM) was N6-(3-(4-chlorophenoxy)propyl)-2-(furan-2-yl)-1,2-dihydro-1,3,5-triazine-4,6-diamine hydrochloride.


Subject(s)
Antimalarials/pharmacology , Plasmodium falciparum/drug effects , Triazines/pharmacology , Antimalarials/chemical synthesis , Antimalarials/chemistry , Molecular Structure , Parasitic Sensitivity Tests , Stereoisomerism , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...