Browsing by Author "Prakash Saudagar"

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Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani
(2013) Sudipta Hazra; Subhalakshmi Ghosh; Madhushree Das Sarma; Smriti Sharma; Mousumi Das; Prakash Saudagar; Vijay Kumar Prajapati; Vikash Kumar Dubey; Shyam Sundar; Banasri Hazra
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 (IC50~20.7μM), and also against normal BALB/c mice in vivo. The compound showed enhanced activity (IC50~7.2μM) as compared to diospyrin (IC50~12.6μM) 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 (IC50~0.18μM). 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. © 2013 Elsevier Inc.
In vivo assessment of antileishmanial property of 4-(4,4,8-trimethyl-7-oxo- 3-oxabicyclo[3.3.1]non-2-yl)-benzoic acid methyl ester, an oxabicyclo[ 3.3.1]nonanones
(Bentham Science Publishers B.V., 2014) Prakash Saudagar; Shyam Lal Mudavath; Pipas Saha; Anil K. Saikia; Shyam Sundar; Vikash Kumar Dubey
The high toxicity and the growing resistance are the major drawbacks of available antileishmanials. Our previous in vitro studies have identified oxabicyclo[3.3.1]nonanones as antileishmanial agents that act on the redox enzymes of the parasite. In the current study, antileishmanial activity of 4-(4,4,8-trimethyl-7-oxo-3-oxabicyclo[3.3.1]non-2-yl)-benzoic acid methyl ester (PS 203) the most potent oxabicyclo[3.3.1]nonanone identified in our previous study is evaluated using the hamster model. There was 77.29 ± 3.0 % inhibition of parasite growth observed after a 5-day treatment of 5 mg/kg body weight dose. Further, the in vivo toxicity study of the compound in Swiss albino mice revealed no hepatic or renal toxicity. © 2014 Bentham Science Publishers.
Miltefosine-unresponsive Leishmania donovani has a greater ability than miltefosine-responsive L. donovani to resist reactive oxygen species
(2013) Mousumi Das; Prakash Saudagar; Shyam Sundar; Vikash K. Dubey
Resistance of Leishmania parasites to miltefosine, which is only available oral drug, is a great concern. We have analyzed global gene expression profiles of miltefosine-unresponsive and miltefosine-responsive Leishmania donovani in order to understand the various metabolic processes involved in miltefosine drug resistance. The microarray data clearly indicated a role of oxidative metabolism in miltefosine resistance. Furthermore, fluorescence microscopy experiments suggested that miltefosine-unresponsive L. donovani resists the accumulation of reactive oxygen species and subsequent mitochondrial membrane damage leading to apoptotic death. In contrast, in miltefosine-responsive L. donovani, the accumulation of reactive oxygen species causes apoptotic death. Overall, this study provides fundamental insights into miltefosine resistance in L. donovani. Database The microarray data have been deposited in the Gene Expression Omnibus database under the accession number GSE45496 We have analyzed global gene expression profiles of miltefosine-unresponsive and miltefosine-responsive Leishmania donovani in order to understand various metabolic processes involved in miltefosine drug resistance. The microarray data clearly indicated a role of oxidative metabolism in miltefosine resistance. The experimental data supports that the miltefosine unresponsive Leishmania donovani can resists formation of reactive oxygen species more efficiently. © 2013 FEBS.