Inhibition of monoamine oxidase by C5-substituted phthalimide analogues.
Summary of "Inhibition of monoamine oxidase by C5-substituted phthalimide analogues."
Literature reports that isatin as well as C5- and C6-substituted isatin analogues are reversible inhibitors of human monoamine oxidase (MAO) A and B. In general, C5- and C6-substitution of isatin leads to enhanced binding affinity to both MAO isozymes compared to isatin and in most instances result in selective binding to the MAO-B isoform. Crystallographic and modeling studies suggest that the isatin ring binds to the substrate cavities of MAO-A and -B and is stabilized by hydrogen bond interactions between the NH and the C2 carbonyl oxygen of the dioxoindolyl moiety and water molecules present in the substrate cavities of MAO-A and -B. Based on these observations and the close structural resemblances between isatin and its phthalimide isomer, a series of phthalimide analogues were synthesized and evaluated as MAO inhibitors. While phthalimide and N-aryl-substituted phthalimides were found to be weak MAO inhibitors, phthalimide homologues containing C5 substituents were potent reversible inhibitors of recombinant human MAO-B with IC(50) values ranging from 0.007 to 2.5μM and moderately potent reversible inhibitors of recombinant human MAO-A with IC(50) values ranging from 0.22 to 9.0μM. By employing molecular docking the importance of hydrogen bonding between the active sites of MAO-A and -B and the phthalimide inhibitors are highlighted.
Affiliation
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Journal Details
This article was published in the following journal.
Name: Bioorganic & medicinal chemistry
ISSN: 1464-3391
Pages: 4829-40
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21778064
- DOI: http://dx.doi.org/10.1016/j.bmc.2011.06.070
Medical and Biotech [MESH] Definitions
Moclobemide
A reversible inhibitor of monoamine oxidase type A; (RIMA); (see MONOAMINE OXIDASE INHIBITORS) that has antidepressive properties.
Monoamine Oxidase
An enzyme that catalyzes the oxidative deamination of naturally occurring monoamines. It is a flavin-containing enzyme that is localized in mitochondrial membranes, whether in nerve terminals, the liver, or other organs. Monoamine oxidase is important in regulating the metabolic degradation of catecholamines and serotonin in neural or target tissues. Hepatic monoamine oxidase has a crucial defensive role in inactivating circulating monoamines or those, such as tyramine, that originate in the gut and are absorbed into the portal circulation. (From Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 8th ed, p415) EC 1.4.3.4.
Furazolidone
A nitrofuran derivative with antiprotozoal and antibacterial activity. Furazolidone acts by gradual inhibition of monoamine oxidase. (From Martindale, The Extra Pharmacopoeia, 30th ed, p514)
Benzylamine Oxidase
An aspect of monoamine oxidase, EC 1.4.3.4. Catalyzes the oxidation of benzylamine to form benzaldehyde, ammonia and hydrogen peroxide.
Pargyline
A monoamine oxidase inhibitor with antihypertensive properties.
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