title: QSAR guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids.
abstract: Naphthylisoquinoline alkaloids have attracted considerable interest because of their intriguing structure, their unique biosynthetic origin, and their biological activities against several pathogens causing tropical diseases. Their promising pharmacologic properties make them suitable lead structures for new agents, in particular against malaria. Since these natural products are not easy to isolate in sufficient quantities or to synthesize stereoselectively, quantitative structure-activity relationship studies were accomplished to find new antiplasmodial analogs that are structurally related to the naturally occurring naphthylisoquinoline alkaloids, but more easily accessible, more active against Plasmodium falciparum, and, last but not least, less toxic. We report on the synthesis of several simplified compounds by a Suzuki coupling between the naphthalene and the isoquinoline moieties and on their activities against different pathogens causing infectious diseases. Some structures were found to exhibit excellent--and selective--activities against P. falciparum in vitro.
authors.affiliation: Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany. bringman@chemie.univ-wuerzburg.de
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.forename: Sebastian K
authors.initials: SK
authors.lastname: Bischof
authors.forename: Steffen
authors.initials: S
authors.lastname: Müller
authors.forename: Tanja
authors.initials: T
authors.lastname: Gulder
authors.forename: Christian
authors.initials: C
authors.lastname: Winter
authors.forename: August
authors.initials: A
authors.lastname: Stich
authors.forename: Heidrun
authors.initials: H
authors.lastname: Moll
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Jan
authors.initials: J
authors.lastname: Dreher
authors.forename: Knut
authors.initials: K
authors.lastname: Baumann
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D007546:Isoquinolines