Discovery of Novel Antileishmanial Agents in an Attempt to Synthesize Pentamidine−Aplysinopsin Hybrid Molecule

In an attempt to synthesize pentamidine−aplysinopsin hybrid molecule 25, a lead molecule 8 (containing Z-configured aplysinopsin moiety) was identified for antileishmanial activity. Optimization of lead 8 provided 24 (containing E-configured aplysinopsin) possessing 10 times more activity and 401-fo...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-10, Vol.52 (19), p.5793-5802
Main Authors: Porwal, Sharad, Chauhan, Shikha S, Chauhan, Prem M. S, Shakya, Nishi, Verma, Aditya, Gupta, Suman
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiparasitic agents
Antiprotozoal Agents - chemical synthesis
Biological and medical sciences
Cell Line
Drug Discovery
Indoles - chemistry
Inhibitory Concentration 50
Leishmania donovani - drug effects
Macrophages - parasitology
Medical sciences
Mice
Parasitic Sensitivity Tests
Pentamidine - chemistry
Pharmacology. Drug treatments
Structure-Activity Relationship
Tryptophan - analogs & derivatives
Tryptophan - chemistry
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Summary:In an attempt to synthesize pentamidine−aplysinopsin hybrid molecule 25, a lead molecule 8 (containing Z-configured aplysinopsin moiety) was identified for antileishmanial activity. Optimization of lead 8 provided 24 (containing E-configured aplysinopsin) possessing 10 times more activity and 401-fold less toxicity than the drug pentamidine in cell based assays. Synthesis of 24 was possible, surprisingly, because of two innate reactivities of indole-3-carbaldehyde which provided it in diastereo- and regio-selectively pure form without recourse to the long reaction pathway.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900564x