ArticleAntimicrobial agents and chemotherapy2016
A Novel Spirooxindole Derivative Inhibits the Growth of Leishmania donovani Parasites both In Vitro and In Vivo by Targeting Type IB Topoisomerase.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Molecular docking: a computational approach for the discovery of novel targets against visceral leishmaniasis.Journal of molecular modeling · 2026Review
- Therapeutic potential of spiro compounds againstRSC medicinal chemistry · 2025Review
- Spiro heterocycles bearing piperidine moiety as potential scaffold for antileishmanial activity: synthesis, biological evaluation, andJournal of enzyme inhibition and medicinal chemistry · 2023Article
- Article
- Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies.Molecules (Basel, Switzerland) · 2023Article
- Recent Advances in Chemotherapeutics for Leishmaniasis: Importance of the Cellular Biochemistry of the Parasite and Its Molecular Interaction with the Host.Pathogens (Basel, Switzerland) · 2023Review
- Hierarchical Clustering and Target-Independent QSAR for Antileishmanial Oxazole and Oxadiazole Derivatives.International journal of molecular sciences · 2022Article
- An insight into the recent developments in anti-infective potential of indole and associated hybrids.Journal of molecular structure · 2022Review
- Metabolic Pathways ofPharmaceutics · 2022Review
- Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis.Molecules (Basel, Switzerland) · 2022Review
- Highly diastereoselective cascade [5 + 1] double Michael reaction, a route for the synthesis of spiro(thio)oxindoles.Scientific reports · 2021Article
- A Series of Isatin-Hydrazones with Cytotoxic Activity and CDK2 Kinase Inhibitory Activity: A Potential Type II ATP Competitive Inhibitor.Molecules (Basel, Switzerland) · 2020Article
- An overview of biochemically characterized drug targets in metabolic pathways of Leishmania parasite.Parasitology research · 2020Review
- In Vitro and in Vivo Activity of mTOR Kinase and PI3K Inhibitors AgainstMolecules (Basel, Switzerland) · 2020Article
- 3',4'-Dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones as potential anti-cancer agents: synthesis and preliminary screening.Royal Society open science · 2020Article
- Neutral Porphyrin Derivative Exerts Anticancer Activity by Targeting Cellular Topoisomerase I (Top1) and Promotes Apoptotic Cell Death without Stabilizing Top1-DNA Cleavage Complexes.Journal of medicinal chemistry · 2018Article
- Recent Advances in the Synthesis of Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis.Molecules (Basel, Switzerland) · 2017Review
- Diastereoselective Synthesis of Spirocyclopropanes under Mild Conditions via Formal [2 + 1] Cycloadditions Using 2,3-Dioxo-4-benzylidene-pyrrolidines.Molecules (Basel, Switzerland) · 2017Article
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8 authors.
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Abstract
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 the 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 a competitive manner. Unlike camptothecin (CPT), the compound does not stabilize the DNA-topoisomerase IB cleavage complex; rather, it hinders drug-DNA-enzyme covalent complex formation. Fluorescence studies show that the 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 the binding site, one in the small subunit and the other in the hinge region of the large subunit of LdTopIB. This spirooxindole is highly cytotoxic to promastigotes of L. donovani and also induces apoptosis-like cell death in the 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 of an effect on host macrophages. Moreover, compound 4c showed strong antileishmanial efficacies in the BALB/c mouse model of leishmaniasis. This compound potentially can be used as a lead for developing excellent antileishmanial agents against emerging drug-resistant strains of the parasite.
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