Reference : Synthesis, cytotoxicity, and antiplasmodial and antitrypanosomal activity of new neoc...
Scientific journals : Article
Life sciences : Multidisciplinary, general & others
Synthesis, cytotoxicity, and antiplasmodial and antitrypanosomal activity of new neocryptolepine derivatives.
Jonckers, Tim H M [> > > >]
van Miert, Sabine [> > > >]
Cimanga, Kanyanga [> > > >]
Bailly, Christian [> > > >]
Colson, Pierre mailto [Université de Liège - ULiège > Département de chimie (sciences) > Département de chimie (sciences) >]
De Pauw-Gillet, Marie-Claire mailto [Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie - Département des sciences biomédicales et précliniques >]
van den Heuvel, Hilde [> > > >]
Claeys, Magda [> > > >]
Lemiere, Filip [> > > >]
Esmans, Eddy L [> > > >]
Rozenski, Jef [> > > >]
Quirijnen, Ludo [> > > >]
Maes, Louis [> > > >]
Dommisse, Roger [> > > >]
Lemiere, Guy L F [> > > >]
Vlietinck, Arnold [> > > >]
Pieters, Luc [> > > >]
Journal of Medicinal Chemistry
American Chemical Society
Yes (verified by ORBi)
[en] Alkaloids/chemical synthesis/pharmacology/toxicity ; Animals ; Antimalarials/chemical synthesis/pharmacology/toxicity ; Cell Line ; DNA/chemistry ; DNA Topoisomerases, Type II/antagonists & inhibitors ; Heme/chemistry ; Hemin/chemistry ; Humans ; Intercalating Agents/chemical synthesis/pharmacology/toxicity ; Plasmodium falciparum/drug effects ; Polymers ; Quinolines/chemical synthesis/pharmacology/toxicity ; Spectrometry, Mass, Electrospray Ionization ; Structure-Activity Relationship ; Trypanocidal Agents/chemical synthesis/pharmacology/toxicity ; Trypanosoma brucei brucei/drug effects ; Trypanosoma cruzi/drug effects
[en] On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting from easily accessible educts, this approach allowed the synthesis of hitherto unknown compounds with a varied substitution pattern. As a result of steric hindrance, preferential formation of the 3-substituted isomers over the 1-substituted isomers was observed when cyclizing N-(3-substituted-phenyl)-N'-[2-(2-trimethylsilylethynyl)phenyl]carbodiimides. All compounds were evaluated for their activity against chloroquine-sensitive as well as chloroquine-resistant Plasmodium falciparum strains, for their activity against Trypanosoma brucei and T. cruzi, and for their cytotoxicity on human MRC-5 cells. Mechanisms of action were investigated by testing heme complexation using ESI-MS, inhibition of beta-hematin formation, DNA interactions (DNA-methyl green assay and linear dichroism), and inhibition of human topoisomerase II. Neocryptolepine derivatives with a higher antiplasmodial activity and a lower cytotoxicity than the original lead have been obtained. This selective antiplasmodial activity was associated with inhibition of beta-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC(50) value against chloroquine-resistant P. falciparum of 4.0 microM in the absence of cytotoxicity (IC(50) > 32 microM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC(50) = 2.0 microM), 2-bromoneocryptolepine showed a low affinity for DNA and no inhibition of human topoisomerase II, in contrast to cryptolepine. Although some neocryptolepine derivatives showed a higher antiplasmodial activity than 2-bromocryptolepine, these compounds also showed a higher affinity for DNA and/or a more pronounced cytotoxicity. Therefore, 2-bromoneocryptolepine is considered as the most promising lead from the present work for new antimalarial agents. In addition, 2-bromo-, 2-nitro-, and 2-methoxy-9-cyanoneocryptolepine exhibited antitrypanosomal activity in the micromolar range in the absence of obvious cytotoxicity.

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