Synthesis and in vitro evaluation of pteridine analogues as monoamine oxidase B and nitric oxide synthase inhibitors.
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.
Prins
Louis H A
LH
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Petzer
Jacobus P
JP
Malan
Sarel F
SF
D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010215:Papio; D011621:Pteridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D011621:Pteridines; D019001:Nitric Oxide Synthase; D008995:Monoamine Oxidase