ABSTRACT
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 (microM) 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 microM 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).
Subject(s)
Benzofurans/chemistry , Benzofurans/pharmacology , Indoles/chemistry , Indoles/pharmacology , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Benzofurans/chemical synthesis , Humans , Indoles/chemical synthesis , Models, Molecular , Monoamine Oxidase Inhibitors/chemical synthesis , Parkinson Disease/drug therapy , Structure-Activity RelationshipABSTRACT
Monoamine oxidase B (MAO-B) and nitric oxide synthase (NOS) have both been implicated in the pathology of neurodegenerative diseases. In an attempt to design dual-target-directed drugs that inhibit both these enzymes, a series of pteridine-2,4-dione analogues were synthesised. The compounds were found to be relatively weak NOS inhibitors but showed promising MAO-B activity with 6-amino-5-[(E)-3-(3-chloro-phenyl)-prop-2-en-(E)-ylideneamino]-1,3-dimethyl-1H-pyrimidine-2,4-dione and 6-[(E)-2-(3-chloro-phenyl)-vinyl]-1,3-dimethyl-1H-pteridine-2,4-dione inhibiting MAO-B with IC(50) values of 0.602 and 0.314 microM, respectively. The pteridine-2,4-dione analogues thus show promise as scaffolds for the development of potent reversible MAO-B inhibitors and as observed in earlier studies, the most potent inhibitors were obtained with 3-chlorostyryl substitution.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase/chemistry , Neuroprotective Agents/chemical synthesis , Nitric Oxide Synthase/antagonists & inhibitors , Pteridines/chemical synthesis , Animals , Binding Sites , Catalytic Domain , Computer Simulation , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Conformation , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase/metabolism , Papio , Pteridines/chemistry , Pteridines/pharmacologyABSTRACT
The blood-brain barrier is formed by the brain capillary endothelium and plays the predominant role in controlling the passage of substances between the blood and the brain. Recent studies on polycyclic structures, i.e. pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane and amantadine, indicated favourable distribution thereof to the brain and it was concluded that these polycyclic structures and their derivatives penetrate the blood-brain barrier readily. A series of novel polycyclic prodrugs incorporating the well known non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid and ibuprofen, were synthesised and screened for blood-brain barrier permeability and antioxidant activity. Increased levels of both NSAIDs were detected in the brain tissue of C57BL/6 mice after administration of the synthesised prodrugs, indicating favourable blood-brain barrier permeation. Results from a lipid peroxidation assay indicated that the ester and amide prodrugs significantly increased the ability of the drugs to attenuate lipid peroxidation. These novel prodrugs thus readily penetrate the blood-brain barrier and exhibit increased antioxidant activity when compared to the free NSAIDs.