title: 2-(3-aryl-3-oxopropen-1-yl)-9-tert-butyl-paullones: a new antileishmanial chemotype.
abstract: A screening program directed to find new agents against Leishmania donovani, the parasite causing visceral leishmaniasis, revealed that paullones attenuate the proliferation of axenic amastigotes. Because these structures were not active in a test system involving infected macrophages, a structure optimization campaign was carried out. Concomitant introduction of an unsaturated side chain into the 2-position and a tert-butyl substituent into the 9-position of the parent scaffold led to compounds inhibiting also parasites dwelling in macrophages. By inclusion of the so elaborated scaffold into a chalcone substructure, the toxicity against uninfected host cells was significantly reduced. For the synthesis of this new compound class, a novel modification of the Heck-type palladium-catalyzed C,C-cross coupling strategy was used, employing a ketone Mannich base as precursor for the alkene reactant. The so-prepared compounds exhibited improved antileishmanial activity both on axenic amastigotes (GI50 < 1 microM) as well as on parasites in infected macrophages.
authors.affiliation: Technische Universität Braunschweig, Institut für Pharmazeutische Chemie, Beethovenstrasse 55, Braunschweig, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Reichwald
authors.forename: Orly
authors.initials: O
authors.lastname: Shimony
authors.forename: Ute
authors.initials: U
authors.lastname: Dunkel
authors.forename: Nina
authors.initials: N
authors.lastname: Sacerdoti-Sierra
authors.forename: Charles L
authors.initials: CL
authors.lastname: Jaffe
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
chemical_list: D001552:Benzazepines; D007211:Indoles; D014344:Trypanocidal Agents