Antimalarial dyes revisited: xanthenes, azines, oxazines, and thiazines

Abstract

In 1891 Guttmann and Ehrlich (P. Guttmann and P. Ehrlich, Berlin Klin. Wochenschr. 28:953-956, 1891) were the first to report the antimalarial properties of a synthetic, rather than a natural, material when they described the clinical cure of two patients after oral administration of a thiazine dye, methylene blue. Since that time, sporadic reports of the antimalarial properties of several xanthene and azine dyes related to methylene blue have been noted. We report here the results from a reexamination of the antimalarial properties of methylene blue, Janus green B, and three rhodamine dyes and disclose new antimalarial data for 16 commercially available structural analogs of these dyes. The 50% inhibitory concentrations for the chloroquinesusceptible D6 clone and SN isolate and the chloroquine-resistant W2 clone of Plasmodium falciparum were determined by the recently described parasite lactate dehydrogenase enzyme assay. No cross-resistance to chloroquine was observed for any of the dyes. For the 21 dyes tested, no correlation was observed between antimalarial activity and cytotoxicity against KB cells. No correlation between log P (where P is the octanol/ water partition coefficient) or relative catalyst efficiency for glucose oxidation and antimalarial activity or cytotoxicity was observed for the dyes as a whole or for the thiazine dyes. The thiazine dyes were the most uniformly potent structural class tested, and among the dyes in this class, methylene blue was notable for both its high antimalarial potency and selectivity.In 1891 Guttmann and Ehrlich (25) were the first to report the antimalarial properties of a synthetic, rather than a natural, material when they described the clinical cure of two patients after oral administration of a thiazine dye, methylene blue. The only side effect that they noted was a ''spastic irritation of the bladder,'' which was partially alleviated by the administration of powdered nutmeg. They selected methylene blue because it had been previously demonstrated by Celli and Guarnieri to specifically stain plasmodia (25) and also because Ehrlich and Leppmann had prior experience in the therapeutic use of this dye in the successful clinical treatment of neuralgias (32). Guttmann and Ehrlich (25) apparently made no further attempt to pursue this interesting observation, although as late as 1956, Dale (14), in his introduction to The Collected Papers of Paul Ehrlich, noted that ''methylene blue itself has there [in the Balkan countries] retained a fairly extensive use, for the treatment of malaria in cases which have been found refractory to quinine.'' Moreover, methylene blue, along with quinine, served as structural prototypes (48) which led to the subsequent development of the 8-aminoquinoline pamaquine and the 9-aminoacridine mepacrine (quinacrine) in 1925 and 1930, respectively (Fig. 1).In the past decade, sporadic reports (7,18,19,21,27) of the antimalarial properties of several xanthene (rhodamines 123, 6G, and B) and azine (Janus green B) dyes related to methylene blue ha...

Blood schizontocidal activity of methylene blue in combination with antimalarials againstPlasmodium falciparum

“…M ethylene blue has already been shown to be active alone in vitro against laboratory-adapted strains from various geographic regions, with IC 50 ranging from 3 to 11 nM (Atamna et al, 1996;Vennerstrom et al, 1995). Our results further demonstrated the in vitro activity of MB against F32 and HB3 chloroquine-sensitive strains, and FcM29 and FcB1 chloroquine-resistant strains of P. falciparum with the same range of activity (~5 nM).…”

Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue

“…The reduced form of MB, which acts as an electron donor, can reverse this oxidation. Against Plasmodium, the mode of action remains enigmatic (36,37). The hypothesis that this highly selective, redox-cycling agent interfered with glutathione reductase was recently refuted by the demonstration that MB was equally active against P. falciparum parasites lacking this antioxidant enzyme (38).…”

“…Such a mode of action would be similar to 4-aminoquinolines such as chloroquine or amodiaquine. However, mechanisms of resistance to those drugs, mediated by the multidrug transporters PfCRT and PfMDR1 (40,41), do not impart cross-resistance to MB (36,42), and a separate mode of action must underlie MB activity against mature gametocytes in which hemoglobin degradation no longer occurs. Given that these forms are often refractory to antimalarial drugs, our data suggest that MB or a derivative thereof could be a highly effective transmission-blocking adjunct to curative antimalarial combinations.…”

Photodynamic antimicrobial chemotherapy (PACT) for the treatment of malaria, leishmaniasis and trypanosomiasis

“…However, several close analogues have been shown to be active against the malarial parasite (39), and several of these have also been examined for blood product decontamination protocols (40). Such work is given special significance by the increasing problem of malarial chloroquine resistance.…”