2-(3-Aryl-3-oxopropen-1-yl)-9-tert-butyl-paullones: A new antileishmanial chemotype

Christina Reichwald, Orly Shimony, Ute Dunkel, Nina Sacerdoti-Sierra, Charles L. Jaffe, Conrad Kunick*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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 μM) as well as on parasites in infected macrophages.

Original languageAmerican English
Pages (from-to)659-665
Number of pages7
JournalJournal of Medicinal Chemistry
Volume51
Issue number3
DOIs
StatePublished - 14 Feb 2008

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