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QSAR guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids.

European journal of medicinal chemistry (2010-09-21)
Gerhard Bringmann, Sebastian K Bischof, Steffen Müller, Tanja Gulder, Christian Winter, August Stich, Heidrun Moll, Marcel Kaiser, Reto Brun, Jan Dreher, Knut Baumann
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Podophyllotoxin
Sigma-Aldrich
Miltefosine, ≥98% (perchloric acid titration)