An evaluation of synthetic indole derivatives as inhibitors of monoamine oxidase (original) (raw)
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Drug Development Research, 2019
In recent studies, we have investigated the monoamine oxidase (MAO) inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives. Since numerous high potency MAO inhibitors are present among these chemical classes, the present study synthesizes 44 additional derivatives in an attempt to further derive structure-activity relationships (SARs) and to establish optimal substitution patterns for MAO inhibition. The results show that, with the exception of one compound, all indole-5,6-dicarbonitrile derivatives (10) exhibit submicromolar IC 50 values for the inhibition of MAO, with the most potent MAO-A inhibitor exhibiting an IC 50 value of 0.006 μM while the most potent MAO-B inhibitor exhibits an IC 50 value of 0.058 μM. Interestingly, an N-oxide derivative (4c) also proved to be a potent and nonspecific MAO inhibitor. With the exception of one compound, all of the pyrrolo [3,4-f]indole-5,7-diones (28) also exhibit submicromolar IC 50 values for the inhibition of an MAO isoform. The most potent inhibitor exhibit an IC 50 value of 0.011 μM for MAO-A. This study proposes that high potency MAO inhibitors such as those investigated here, may act as lead compounds for the development of treatments for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression.
Drug Development Research, 2018
In recent studies, we have shown that pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives act as good potency in vitro inhibitors of the monoamine oxidase (MAO) enzymes. To expand on these series and to further derive structure-activity relationships (SARs) for MAO inhibition, in the present study we synthesized additional homologs and related analogs of these chemical classes. Analyzes of the MAO inhibition properties of the synthesized compounds show that among the pyrrolo[3,4-f]indole-5,7-dione derivatives good potency MAO inhibitors exist as exemplified by 10, which possesses IC 50 values for the inhibition of MAO-A and MAO-B of 0.023 and 0.178 mM, respectively. Among thirteen pyrrolo[3,4-f]indole-5,7-diones, nine compounds exhibit IC 50 values for the inhibition of an MAO isoform in the submicromolar range. It may be concluded that active MAO inhibitors, such as 10 represent suitable leads for the development of drugs for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. MAO inhibitors are also of interest for the treatment of prostate cancer, certain types of cardiomyopathies and Alzheimer's disease.
Inhibition of monoamine oxidase by indole and benzofuran derivatives
European Journal of Medicinal Chemistry, 2010
Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. A series of indole and benzofuran derivatives were synthesised and evaluated as inhibitors of the two MAO isoforms, MAO-A and MAO-B. In general, the derivatives were found to be selective MAO-B inhibitors with K i values in the nanoMolar (nM) to microMolar (mM) concentration range. The most potent MAO-B inhibitor, 3,4-dichloro-N-(2-methyl-1H-indol-5-yl)benzamide, exhibited a K i value of 0.03 mM and was 99 fold more selective for the B isoform. We conclude that these indole and benzofuran derivatives are promising reversible MAO-B inhibitors with a possible role in the treatment of neurodegenerative diseases such as Parkinson's disease (PD).
QSAR Analysis of Indole Analogues as Monoamine Oxidase Inhibitors
Journal of Chemical Information and Modeling, 1996
The quantitative structure-activity relationship (QSAR) analysis with comparative molecular field analysis (CoMFA) of indole derivatives-monoamine oxidase (MAO) inhibitors were done. The pharmacophore model included four features: two hydrophobic rings, one donor atom, and one acceptor site. The predictive values (cross-validated r 2 ) of QSAR analysis for the inhibition of MAO-A and MAO-B were 0.743 and 0.603, respectively. The contributions of steric and electrostatic fields in the interaction between inhibitors and enzymes were equal. The three-dimensional arrangement of these fields for MAO-A and MAO-B suggests that structures of active site for both enzymes are considerably differed from each other.
Pharmacological study of new indole derivatives and its biochemical correlates
Pharmacological Research Communications, 1981
Some ~-substituted 2-methyl indole 3-acetyl-N t-(substituted benzyl or isopropyl) hydrazides were synthesized by reduolng N I -2-methyl Indole-3-acetyl-N' -~ substltuted benzylldene or Isopropylldene) hydrazldes and they were cheuractsrized. The compounds were studied for their effect on the monoamine oxtdase activity in vitro. Three compounds showed more than 65~ monoamine oxidaee inhibitory activity at the concentration of I x lO'SM_.
Relevance of benzyloxy group in 2-indolyl methylamines in the selective MAO-B inhibition
British Journal of Pharmacology, 1999
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. 2 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. 3 The K i 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 (K i values of 376+0.032 and 16.8+0.1 nM for MAO A and MAO-B, respectively). The IC 50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150+8 mM for FA-73 and 68+10 mM for L-deprenyl whereas in human caudate tissue the IC 50 values were 0.36+0.015 mM for FA-73 and 0.10+0.007 mM for L-deprenyl. Moreover, mouse brain MAO-B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg 71 adminstration, MAO-A activity was not aected. 4 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-Benzylidene-1-indanone derivatives as inhibitors of monoamine oxidase
Bioorganic & Medicinal Chemistry Letters, 2016
In the present study, a series of twenty-two 2-benzylidene-1-indanone derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The 2benzylidene-1-indanone derivatives are structurally related to a series of benzylideneindanone derivatives which has previously been found to be MAO-B inhibitors. This study finds that the 2benzylidene-1-indanones are MAO-B specific inhibitors with IC 50 values < 2.74 µM. Among the compounds evaluated, twelve compounds exhibited IC 50 < 0.1 µM and may be considered as high potency inhibitors. The 2-benzylidene-1-indanone derivatives also inhibited MAO-A with the most potent inhibition exhibited by 5g (IC 50 = 0.131 µM). An analysis of the structure-activity relationships for MAO-B inhibition show that substitution on the A-ring with a 5-hydroxy group and on the Bring with halogens and the methyl group yield high potency inhibition. It may therefore be concluded that 2-benzylidene-1-indanone analogues are promising leads for design of therapies for disorders such as Parkinson's disease.
New indolyl peptidyl esters as MAO inhibitors
Pharmacological Research Communications, 1982
Substituted indol~;-3-peptidyl esters were synthesized and were characterized. The compounds were studied for their effect on the monoamine oxldase activity both in vitro as well as in vlvo and compared with known MAO inhlbltors such as tranylcypromine. Approximate lethal dose (ALD/50) of the compounds was also determined. INTR ODUCTI ON Several studies have adduced evidence to show that a steady state level of bloge[tic amines e.g. noradrenallne (N~') adrenaline (AD), dopamine (DA) and 5-hydroxytryptamine (5-~£) is of prime importance for the normal functioning of CNS. Furthermore, a decrease in the level of these a, lnes has been implicated in the pathogenesis of effective disorders llke depression. One of the main approach which has yielded beneficial result is the discovery of substances which can successfully inhibit the metabolism of these amines at the cellular level i.e. termination of action of these amines is largely due to the oxidative de,ruination by the enzyme monoamlne oxldase (MAO). More recently specific inhibitors 3 of this enzyme , are being searched of since it is reported