A novel spirooxindole derivative inhibits the growth of Leishmania donovani parasite both in vitro and in vivo by targeting type IB topoisomerase
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
A novel spirooxindole derivative inhibits the growth of Leishmania donovani parasite both in vitro and in vivo by targeting type IB topoisomerase
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| Creator |
Saha, Sourav
Acharya, Chiranjit Pal, Uttam Roy Chowdhury, Somenath Sarkar, kahini Maiti, Nakul Chandra Jaisankar , P Majumder, Hemanta K |
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| Subject |
Chemistry
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| Description |
Visceral Leishmaniasis is a fatal parasitic disease and there is an emergent need for development of effective drugs against this neglected tropical disease. We report here development of a novel spirooxindole derivative N-benzyl 2, 2’ α 3, 3’, 5’, 6’, 7’, 7α,α'-octahydro-2methoxycarbonyl-spiro [indole-3, 3’ -pyrrolizidine]-2 one (Compound 4c) which inhibits Leishmania donovani topoisomerase IB (LdTopIB) and kills the wild type as well as drug-resistant parasite strains. This compound inhibits catalytic activity of LdTopIB in competitive manner. Unlike Camptothecin, the compound does not stabilize the DNA-topoisomerase IB cleavage complex; rather, they hinder drug-DNA-enzyme covalent complex formation. Fluorescence studies show stoichiometry of this compound binding to LdTopIB is 2:1 (mole/mole) with a dissociation constant of 6.65 μM. Molecular docking with LdTopIB using the stereoisomers of Compound 4c produced two probable hits for binding site: one in small subunit and the other in the hinge region of the large subunit of LdTopIB. This spirooxindole is highly cytotoxic to promastogotes of L. donovani and also induces apoptosis-like cell death in parasite. Treatment with compound 4c causes depolarization of mitochondrial membrane potential, formation of reactive oxygen species inside parasites and ultimately fragmentation of nuclear DNA. Compound 4c also effectively clears amastigote forms of wild type and drug-resistant parasites from infected mouse peritoneal macrophages but has less effect on host macrophages. Moreover compound 4c showed strong antileishmanial efficacies in BALB/c mice model of leishmaniasis. Potentially this compound can be used as a lead for developing excellent anileishmanial agent against emerging drug resistant strains of the parasite.
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| Publisher |
American Society for Microbiology
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| Date |
2016
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2544/1/Antimicrob._Agents_Chemother.%2D2016%2DSaha%2D6281%2D93.pdf
Saha, Sourav and Acharya, Chiranjit and Pal, Uttam and Roy Chowdhury, Somenath and Sarkar, kahini and Maiti, Nakul Chandra and Jaisankar , P and Majumder, Hemanta K (2016) A novel spirooxindole derivative inhibits the growth of Leishmania donovani parasite both in vitro and in vivo by targeting type IB topoisomerase. Antimicrobial Agents and Chemotherapy, 60 (10). pp. 6281-6293. |
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| Relation |
http://aac.asm.org/content/60/10/6281.full.pdf+html
http://www.eprints.iicb.res.in/2544/ |
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