Abstract
BackgroundBasic blue 3 is a promising anti-malarial lead compound based on the π-delocalized lipophilic cation hypothesis. Its derivatives with nitrogen atoms bonded to carbon atoms at the 3- and 7-positions on the phenoxazine ring were previously shown to exert potent antiprotozoal activity against Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei rhodesiense, and Leishmania donovani parasites in vitro. However, compounds with nitrogen modification at the 10-position on the phenoxazine ring were not evaluated.MethodsSix acylphenoxazine derivatives (ITT-001 to 006) with nitrogen modification at the 10-position on the phenoxazine ring, which were synthesized from basic blue 3, were characterized and evaluated for anti-malarial activity in vitro with an automated haematology analyzer (XN-30) and light microscopy. Intensity of self-fluorescence was measured using a fluorometer. Localization of basic blue 3 was observed by fluorescence microscopy. Cytotoxicity was evaluated using human cell lines, HEK293T and HepG2 cells. Finally, anti-malarial activity was evaluated in a rodent malaria model.ResultsAll the six derivatives showed anti-malarial efficacy even against chloroquine-, pyrimethamine-, and artemisinin-resistant field isolates similar to the sensitive strains and isolates in vitro. The efficacy of basic blue 3 was the strongest, followed by that of ITT-001 to 004 and 006, while that of ITT-005 was the weakest. Basic blue 3 showed strong self-fluorescence, whereas ITT derivatives had five- to tenfold lower intensity than that of basic blue 3, which was shown by fluorescence microscopy to be selectively accumulated in the plasmodial cytoplasm. In contrast, ITT-003, 004, and 006 exhibited the lowest cytotoxicity in HEK293T and HepG2 cells in vitro and the highest selectivity between anti-malarial activity and cytotoxicity. The in vivo anti-malarial assay indicated that oral administration of ITT-004 was the most effective against the rodent malaria parasite, Plasmodium berghei NK65 strain.ConclusionsThe six ITT derivatives were effective against chloroquine- and pyrimethamine-resistant strains and artemisinin-resistant field isolates as well as the sensitive ones. Among them, ITT-004, which had high anti-malarial activity and low cytotoxicity in vitro and in vivo, is a promising anti-malarial lead compound.
Highlights
Basic blue 3 is a promising anti-malarial lead compound based on the π-delocalized lipophilic cation hypothesis
Previous studies reported novel antiprotozoal compounds based on the π-delocalized lipophilic cations (DLC) hypothesis [11,12,13,14,15,16,17], in which hydrophobic cations containing delocalized π-electrons accumulate in the parasite mitochondria and inhibit metabolic activity [18]
Synthesis of ITT derivatives To characterize the effects of the modification of the nitrogen atom at the 10-position on the phenoxazine ring of basic blue 3 [Fig. 1a(i)], six derivatives modified with a variety of acyl groups were synthesized [Fig. 1a(ii), ITT001 to 006]
Summary
Basic blue 3 is a promising anti-malarial lead compound based on the π-delocalized lipophilic cation hypothesis. Its derivatives with nitrogen atoms bonded to carbon atoms at the 3- and 7-positions on the phenoxa‐ zine ring were previously shown to exert potent antiprotozoal activity against Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei rhodesiense, and Leishmania donovani parasites in vitro. Phenoxazinium salt (basic blue 3 in this study) displayed strong antiprotozoal activity with high selectivity [17] For their synthesis, the reactions of m-aminophenols and p-nitrosoanilines in perchloric acid produces very poor yields (2–40%) [17]. Some of their derivatives in which nitrogen atoms are bonded to carbon atoms at the 3- and 7-positions on the phenoxazine ring were modified and showed potent antiprotozoal activity against P. falciparum, Trypanosoma cruzi, Trypanosoma brucei rhodesiense, and Leishmania donovani parasites in vitro [20]. It was discovered that the derivatives have a potential application as reversible near-infrared pH sensors [22]
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