Mode of antimalarial effect of methylene blue and some of its analogues on Plasmodium falciparum in culture and their inhibition of P-vinckei petteri and P-yoelii nigeriensis in vivo
Mode of antimalarial effect of methylene blue and some of its analogues on Plasmodium falciparum in culture and their inhibition of P-vinckei petteri and P-yoelii nigeriensis in vivo
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DOI：
10.1016/s0006-2952(95)02258-9
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发表时间：
1996-03-08
影响因子：
5.8
通讯作者：
Ginsburg, H
中科院分区：
文献类型：
--
作者：
Atamna, H;Krugliak, M;Ginsburg, H
亚甲蓝（MB）的抗疟作用最早由Paul埃利希在世纪末发现。虽然它只是偶尔被用作可用药物，但其抗疟作用的解决似乎是必要的，因为它目前被用于治疗各种高铁血红蛋白血症。在这项工作中，我们使用了MB及其类似物Azures A（AZA）、B（AZB）、C（AZC）和硫堇（TH），以及恶嗪塞莱斯廷蓝（CB）和吖嗪吩噻嗪（PS）。所有MB类似物均能抑制不同恶性疟原虫株在IC（50）培养基中的生长。10（-9）-1。10（-7）M范围，其中等级顺序MB近似为AZA> AZB> AZC> TH> PS> CB。哺乳动物细胞系的IC（50）在3。10（-6）-4。10（-5）M范围，其大小顺序为TH近似AZB> AZA近似PS> AZC近似CB> MB。由于IMB可以通过NADPH的氧化影响细胞生长，我们测试了各种化合物对己糖-磷酸分流活性的作用。在1时观察到明显的分流激活。10（-5）M，因此解释了对哺乳动物细胞生长的抑制作用，但对寄生虫无抑制作用。所有的化合物被发现复杂的血红素在一个类似于其抗疟作用的排名顺序。因此，建议MB及其同系物的行为，防止聚合的血红素，这是在消化宿主细胞胞质溶胶在寄生虫的食物泡，成疟原虫色素。在这方面，这些化合物似乎与4-氨基喹啉抗疟药的作用相似。所有化合物在体内均有效地抑制了P.vinckei petteri的生长，IC 50在1.2 - 5.2 mg/kg范围内，MB和AZB在9 - 11 mg/kg范围内抑制了约氏疟原虫尼日利亚亚种（即在与氯喹相似的剂量下）。这些化合物的潜在毒性可能会限制其临床应用，但其令人印象深刻的抗疟活性表明吩噻嗪结构可以作为进一步药物开发的先导化合物。
The antimalarial action of methylene blue (MB) was first noted by Paul Ehrlich in the late 19th century. Although it has only sporadically been adopted as a serviceable drug, the resolution of its antimalarial action seems warranted, as it is currently used for the treatment of various methemoglobinemias. In this work we have used MB, and its analogues Azures A (AZA), B (AZB), C (AZC), and thionin (TH), as well as the oxazine Celestine blue (CB) and the azine Phenosaphranin (PS). All MB analogues inhibit the growth of various strains of Plasmodium falciparum in culture with IC(50)s in the 2 . 10(-9)-1 . 10(-7) M range, with the rank order MB approximate to AZA > AZB > AZC > TH > PS > CB. The IC(50)s for a mammalian cell line were in the 3 . 10(-6)-4 . 10(-5) M range, and the rank order was TH approximate to AZB > AZA approximate to PS > AZC approximate to CB > MB. As IMB could affect cell growth through the oxidation of NADPH, we tested the action of the various compounds on the hexose-monophosphate shunt activity. Appreciable activation of the shunt was observed at 1 . 10(-5) M in both cell types, thus accounting for inhibition of growth of mammalian cells but not of parasites. All compounds were found to complex with heme in a rank order similar to their antimalarial effect. It is therefore suggested that MB and its congeners act by preventing the polymerization of heme, which is produced during the digestion of host cell cytosol in the parasite food vacuole, into hemozoin. In this respect, these compounds seem to act similarly to the 4-aminoquinoline antimalarials. All compounds effectively suppressed the growth of P. vinckei petteri in vivo with IC50 in the 1.2-5.2 mg/kg range, and MB and AZB suppressed P. yoelii nigeriensis in the 9-11 mg/kg range (i.e. at doses similar to those of chloroquine). The potential toxicity of these compounds may restrict their clinical use, but their impressive antimalarial activities suggest that the phenothiazine structure could serve as a lead compound for further drug development.