ABSTRACT
Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials as treatment for malarial infection, 19 quinone derivatives with previously reported structures were also evaluated for blood schizonticide activity against the malaria parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol (13) and phenazines (12-20). Their cytotoxicities were also evaluated against human hepatoma and normal monkey kidney cell lines. Compounds 2 and 5 showed the highest activity against P. falciparum chloroquine-resistant blood-stage parasites (clone W2), indicated by their low inhibitory concentration for 50% (IC50) of parasite growth. The therapeutic potential of the active compounds was evaluated according to the selectivity index, which is a ratio of the cytotoxicity minimum lethal dose which eliminates 50% of cells and the in vitro IC50. Naphthoquinones 2 and 5, with activities similar to the reference antimalarial chloroquine, were also active against malaria in mice and suppressed parasitaemia by more than 60% in contrast to compound 11 which was inactive. Based on their in vitro and in vivo activities, compounds 2 and 5 are considered promising molecules for antimalarial treatment and warrant further study.
Subject(s)
Animals , Humans , Mice , Antimalarials/pharmacology , Malaria/drug therapy , Naphthoquinones/pharmacology , Phenazines/pharmacology , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Antimalarials/chemistry , Cell Line , Disease Models, Animal , Malaria/parasitology , Naphthoquinones/chemistry , Parasitic Sensitivity Tests , Parasitemia/drug therapy , Phenazines/chemistryABSTRACT
Use of safranine-o has been examined as membrane potential probe in 1-palmitoyl-2-oleoyl-3-phosphatidylcholine (POPC) vesicles both in presence and absence of cholesterol. The fluorescence signal increases in presence of vesicles and the increase in fluorescence intensity on hyperpolarization with valinomycin is diffusion potential dependent. The fluorescence spectra recorded after time driven experiments reveals the blue shift in gamma max of fluorescence with increasing diffusion potential. The fluorescence spectra of vesicles-associated dye is at variance with those of the safranine-o in organic solvents. In organic solvents with increasing hydrophobic character of the solvent the gamma max is slightly red shifted. The electronic spectra of the dye molecule and the charges on different atomic centers have been calculated by quantum chemical method GRINDOL. The predicted first excited state originating from the phenazine moiety is in very good agreement with the excitation wavelength. On the basis of charges on various atoms the binding of safranine with vesicles has been discussed. The nonlinear behaviour of fluorescence signal with delta phi, anisotropy measurements and the computational results, reveal the penetration of bound dye molecules (along with orientation) as a function of diffusion potential. Addition of microaliquots of 1.5 M K2SO4 to already hyperpolarized vesicles decreases the fluorescence signal and the fluorescence spectra recorded on stabilization of signal after each addition showed a shift in gamma max of fluorescence in opposite direction i.e. red shifted.