Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India.
Exp Parasitol. 2013 Oct;135(2):407-13. doi: 10.1016/j.exppara.2013.07.021. Epub 2013 Aug 20.
World health organization has called for academic research and development of new chemotherapeutic strategies to overcome the emerging resistance and side effects exhibited by the drugs currently used against leishmaniasis. Diospyrin, a bis-naphthoquinone isolated from Diospyros montana Roxb., and its semi-synthetic derivatives, were reported for inhibitory activity against protozoan parasites including Leishmania. Presently, we have investigated the antileishmanial effect of a di-epoxide derivative of diospyrin (D17), both in vitro and in vivo. Further, the safety profile of D17 was established by testing its toxicity against normal macrophage cells (IC₅₀∼20.7 μM), and also against normal BALB/c mice in vivo. The compound showed enhanced activity (IC₅₀∼7.2 μM) as compared to diospyrin (IC₅₀∼12.6 μM) against Leishmania donovani promastigotes. Again, D17 was tested on L. donovani BHU1216 isolated from a sodium stibogluconate-unresponsive patient, and exhibited selective inhibition of the intracellular amastigotes (IC₅₀∼0.18 μM). Also, treatment of infected BALB/c mice with D17 at 2mg/kg/day reduced the hepatic parasite load by about 38%. Subsequently, computational docking studies were undertaken on selected enzymes of trypanothione metabolism, viz. trypanothione reductase (TryR) and ornithine decarboxylase (ODC), followed by the enzyme kinetics, where D17 demonstrated non-competitive inhibition of the L. donovani ODC, but could not inhibit TryR.
世界卫生组织呼吁开展学术研究和开发新的化疗策略，以克服目前用于治疗利什曼病的药物所表现出的耐药性和副作用。从柿树 Diospyros montana Roxb. 中分离得到的双萘醌二苯并吡喃酮及其半合成衍生物被报道对原生动物寄生虫包括利什曼原虫具有抑制活性。目前，我们已经研究了二苯并吡喃酮的二环氧衍生物（D17）的抗利什曼原虫作用，包括在体外和体内。此外，通过测试 D17 对正常巨噬细胞（IC₅₀∼20.7 μM）的毒性以及在体内对正常 BALB/c 小鼠的毒性，确定了 D17 的安全性特征。与二苯并吡喃酮（IC₅₀∼12.6 μM）相比，该化合物对利什曼原虫 Donovan 前鞭毛体的活性增强（IC₅₀∼7.2 μM）。此外，D17 还在从对葡甲胺锑酸钠无反应的患者中分离出的 L. donovani BHU1216 上进行了测试，对细胞内无鞭毛体表现出选择性抑制（IC₅₀∼0.18 μM）。同样，用 D17 以 2mg/kg/天的剂量治疗感染的 BALB/c 小鼠可使肝寄生虫负荷减少约 38%。随后，对几种硫醇代谢相关酶，即硫醇还原酶（TryR）和鸟氨酸脱羧酶（ODC）进行了计算机对接研究，并进行了酶动力学研究，结果表明 D17 对 L. donovani ODC 具有非竞争性抑制作用，但不能抑制 TryR。
