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Abstract: The benzo[a]phenoxazine derivative, SSJ-183 has shown excellent anti-malarial efficacy and safety. However, its mechanism of action is unclear. We investigated the effect of SSJ-183 on the rodent malarial parasite, Plasmodium berghei. We analyzed changes in protein expression in the erythrocytic cycle of P. berghei with or without 18h of SSJ-183 treatment by two-dimensional gel electrophoresis. We confirmed results with matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight tandem mass spectrometry. After treatment, seven main proteins were significantly down-regulated, and two were up-regulated; results were reproduced in three independent tests. Some of these proteins were hypothetical parasite proteins or unnamed host products. However, three proteins were identified as a heat shock protein, a disulfide isomerase precursor, and berghepain-2 from P. berghei. All three showed reduced expression after SSJ-183 treatment. This suggested that SSJ-183 was a good anti-malarial drug candidate because it targeted parasite chaperone proteins. [Copyright &y& Elsevier]

Abstract: Tropical diseases are serious infectious diseases caused by protozoan parasites in tropical and subtropical regions. Novel, effective, safe, and inexpensive drugs are required to treat the parasites and contribute to the global goal of eradication. A series of phenothiazinium chlorides were synthesized and evaluated for in vitro activities against Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei rhodesiense, and Leishmania donovani. Notably, 3,7-bis(piperidinyl)phenothiazinium chloride showed IC50 of 0.097 μmol L−1 against T. cruzi and 3,7-bis(benzyl(methyl)amino)phenothiazinium chloride exhibited IC50 of 0.081 μmol L−1 against L. donovani, although the cytotoxicities of these compounds against L-6 cells were observed at low concentration. [ABSTRACT FROM AUTHOR]

Abstract: SSJ-127, a novel antimalarial rhodacyanine derivative, has shown potent antimalarial activity against chloroquine-resistant Plasmodium strains in vitro and subcutaneous administration of SSJ-127 results in a complete cure of a mouse malaria model. SSJ-127 was detected by fluorescence microscopy in the mouse malaria parasites Plasmodium berghei after exposure of infected red blood cells to the compound in vitro and in vivo. Selective accumulation of SSJ-127 in an organelle is observed in all blood stages of live malaria parasites. The organelle is clearly different from the mitochondrion and the nucleus in terms of morphology. The shape of the organelle changed during the asexual blood stages of the parasite. There was always a close association between the organelle and the mitochondrion. These results raised the possibility that SSJ-127 accumulates in an apicoplast of the malaria parasite and affects protozoan parasite-specific pathways. [ABSTRACT FROM AUTHOR]

Abstract: Zinc chloride-free 3,7-bis(dialkylamino)phenoxazinium salts carrying different anions (chloride, bromide, hydrosulfate, tosylate, perchlorate and nitrate) were synthesized with the yields up to 84%. Their structures were determined by spectroscopy and elemental analyses. [Copyright &y& Elsevier]

Abstract: In vivo antimalarial drug candidates screening test was carried out on a series of water-soluble 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives. Among them, 3-(diethylamino)-7-(piperidin-1-yl)phenoxazin-5-ium chloride (SSJ-206) showing highest efficacy was chosen for further pharmcodynamics and pharmacokinetics study. It was supported from these data that the phenoxazinium salts, SSJ-206, would be one of hopeful candidates as an oral antimalarial drug. [Copyright &y& Elsevier]