In vitro antiplasmodial activity and cytotoxicity of newly synthesized N-alkyl and N-benzyl-1,10-phenanthroline derivatives.

A previous study showed that the 1,10-phenanthroline skeleton was active in vitro against chloroquine-resistant and sensitive strains of Plasmodium falciparum. Based on this skeleton, 8 derivatives of N-alkyl and N-benzyl-1,10-phenanthrolines have been synthesized. This study was conducted to evaluate the in vitro antiplasmodial activity and cytotoxicity of these compounds. The in vitro antiplasmodial activity was tested on two strains of P. falciparum, FCR-3 chloroquine-resistant and D10 chloroquine-sensitive strains, while their cytotoxicity was tested on the Vero cell line. The parasite and cell growth were estimated by hypoxantine-[2,8-3H] uptake after 24- and 72-hour incubation with each compound tested. The control parasite or cell free from any compounds was referred to as having 100% growth. For this radioactive method, the IC50 value showing concentration inhibiting 50% of the parasite growth was determined by probit analysis. The results showed that the highest antiplasmodial activity was observed with (1)-N-benzyl-1,10-phenanthrolinium iodide with the IC50 0.18-0.45 microM, and the IC50 of the compound on Vero cells ranged from 2,582.30 to 7,057.71 microM. The cytotoxic/ antiplasmodial ratio indicates that this compound has high selectivity (10,993 +/- 330.79-38,965 +/- 6,888.27).

Killing of blood stage Plasmodium vinckei petteri by spleen macrophages through L-arginine dependent mechanism.

A series of experiments was carried out to investigate the involvement of the L-arginine-dependent effector mechanism (LADEM) in the killing of the blood stages of the rodent malaria parasite, Plasmodium vinckei petteri, by activated spleen macrophages in vitro. P.v.petteri-infected red blood cells were co-incubated with spleen macrophages from normal mice which had previously received 10(8) Mycobacterium bovis (BCG) 5 days earlier, in the presence of 0.1 microgram/ml LPS with and without 0.1 mM L-NMMA, an L-arginine analogue which inhibits LADEM, for 16 hours. The viability of the parasites was assessed according to their infectivity following inoculation into experimental mice. Incubation of parasites with spleen macrophages in the presence of LPS without L-NMMA reduced the parasite viability to about 3%. When L-NMMA was included in the culture, inhibition of parasite killing was observed, resulting in an increase of parasite viability to about 21%. These data provide evidence to suggest that spleen macrophages play an important role as effector cells in the immune mechanisms against P.v.petteri infection, and that the parasite killing of these cells, at least in part, was mediated by LADEM.