title: Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani.
abstract: 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.
authors: Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India.
authors: Sudipta
authors: S
authors: Hazra
authors: Subhalakshmi
authors: S
authors: Ghosh
authors: Madhushree
authors: M
authors: Das Sarma
authors: Smriti
authors: S
authors: Sharma
authors: Mousumi
authors: M
authors: Das
authors: Prakash
authors: P
authors: Saudagar
authors: Vijay Kumar
authors: VK
authors: Prajapati
authors: Vikash Kumar
authors: VK
authors: Dubey
authors: Shyam
authors: S
authors: Sundar
authors: Banasri
authors: B
authors: Hazra
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007893:Leishmania donovani / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D009955:Ornithine Decarboxylase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011897:Random Allocation
chemical_list: D000981:Antiprotozoal Agents; D009285:Naphthoquinones; D065108:Ornithine Decarboxylase Inhibitors; D009955:Ornithine Decarboxylase; C043546:diospyrin
keywords: Antileishmanial agent; Diospyrin; Leishmania donovani; Naphthoquinonoid compounds; Ornithine decarboxylase; Trypanothione reductase