2-7-dibromocryptolepine and Malaria--Falciparum

Density functional theory calculations were applied to investigate (13)C chemical shielding tensors in cryptolepine and its bromo-substituted analogs, 2-bromocryptolepine and 2,7-dibromocryptolepine. The fact that bromo-substituted cryptolepine shows higher antiplasmodial activity than cryptolepine raises the question of whether this effect can be related to the electronic properties around carbon atoms. The results show that changes to the principal components of the shielding tensors upon substitution are significant. In particular, σ (33) is the most affected tensor for carbons in the substituted ring, which could be related to the increased antiplasmodial activity of bromosubstituted cryptolepine. The analyses were also focused on atomic charges and dipole moment.

Topics: Alkaloids; Antimalarials; Bromides; Carbon Isotopes; DNA, Protozoan; Halogenation; Humans; Indole Alkaloids; Indoles; Magnetic Resonance Spectroscopy; Malaria, Falciparum; Models, Molecular; Plasmodium falciparum; Quantum Theory; Quinolines; Static Electricity; Structure-Activity Relationship

A series of mono- and di-substituted analogues of isocryptolepine have been synthesized and evaluated for in vitro antimalarial activity against chloroquine sensitive (3D7) and resistant (W2mef) Plasmodium falciparum and for cytotoxicity (3T3 cells). Di-halogenated compounds were the most potent derivatives and 8-bromo-2-chloroisocryptolepine displayed the highest selectivity index (106; the ratio of cytotoxicity (IC(50)=9005 nM) to antimalarial activity (IC(50)=85 nM)). Our evaluation of novel isocryptolepine compounds has demonstrated that di-halogenated derivatives are promising antimalarial lead compounds.

Topics: 3T3 Cells; Animals; Antimalarials; Chloroquine; Humans; Indole Alkaloids; Malaria, Falciparum; Mice; Plasmodium falciparum; Quinolines; Structure-Activity Relationship