Inhibition of monoamine oxidase by selected C5- and C6-substituted isatin analogues.
Previous studies have shown that (E)-5-styrylisatin and (E)-6-styrylisatin are reversible inhibitors of human monoamine oxidase (MAO) A and B. Both homologues are reported to exhibit selective binding to the MAO-B isoform with (E)-5-styrylisatin being the most potent inhibitor. To further investigate these structure-activity relationships (SAR), in the present study, additional C5- and C6-substituted isatin analogues were synthesized and evaluated as inhibitors of recombinant human MAO-A and MAO-B. With the exception of 5-phenylisatin, all of the analogues examined were selective MAO-B inhibitors. The C5-substituted isatins exhibited higher binding affinities to MAO-B than the corresponding C6-substituted homologues. The most potent MAO-B inhibitor, 5-(4-phenylbutyl)isatin, exhibited an IC(50) value of 0.66nM, approximately 13-fold more potent than (E)-5-styrylisatin and 18,500-fold more potent than isatin. The most potent MAO-A inhibitor was found to be 5-phenylisatin with an IC(50) value of 562nM. The results document that substitution at C5 with a variety of substituents is a general strategy for enhancing the MAO-B inhibition potency of isatin. Possible binding orientations of selected isatin analogues within the active site cavities of MAO-A and MAO-B are proposed.
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Clarina I
CI
Manley-King
Jacobus J
JJ
Bergh
Jacobus P
JP
Petzer
D018360:Crystallography, X-Ray; D007510:Isatin / Q000031:analogs & derivatives / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D007510:Isatin