title: Alkynyl-coumarinyl ethers as MAO-B inhibitors.
abstract: In this study, alkynyl-coumarinyl ethers were developed as inhibitors of human monoamine oxidase B (MAO-B). A series of 31 new, ether-connected coumarin derivatives was synthesized via hydroxycoumarins, whose phenolic group at position 6, 7 or 8 was converted by means of the Mitsunobu reaction. The majority of the final products were produced from primary alcohols with a terminal alkyne group. The inhibitors were optimized with respect to the structure of the alkynyloxy chain and its position at the fused benzene ring as well as the residue at position 3 of the pyran-2H-one part. A hex-5-ynyloxy chain at position 7 was found to be particular advantageous. Among the 7-hex-5-ynyloxy-coumarins, the 3-methoxycarbonyl derivative 36 was characterized as a dual-acting inhibitor with IC₅₀ values of less than 10 nM towards MAO-A and MAO-B, and the 3-(4-methoxy)phenyl derivative 44 was shown to combine strong anti-MAO-B potency (IC₅₀=3.0 nM) and selectivity for MAO-B over MAO-A (selectivity >3400-fold).
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Matthias D
authors.initials: MD
authors.lastname: Mertens
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hinz
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: christa.mueller@uni-bonn.de.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: guetschow@uni-bonn.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D003374:Coumarins; D004987:Ethers; D008996:Monoamine Oxidase Inhibitors; D011994:Recombinant Proteins; C030123:coumarin; D008995:Monoamine Oxidase
keywords: Alkynes; Coumarins; Distribution coefficients; Mitsunobu reaction; Monoamine oxidase