ABSTRACT
A new Heck-type reaction for the synthesis of chalcones has been established using Mannich bases as enone precursors. The novel reaction proceeds rapidly in air atmosphere under ligandless conditions and can be adapted for library synthesis in a parallel reactor station. Screening of the synthesized chalcones revealed N-{4-[(1E)-3-oxo-3-(3-pyridinyl)-1-propenyl]phenyl}benzamide (3f) to be a potent anti-leishmanial agent.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Ketones/chemistry , Leishmania donovani/drug effects , Leishmaniasis/drug therapy , Mannich Bases/chemistry , Animals , Cells, Cultured , Chromatography, High Pressure Liquid , Crystallization , Leishmaniasis/parasitology , Macrophages/cytology , Macrophages/drug effects , Molecular StructureABSTRACT
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.
