Abstract
Cryptolepine derivatives containing alkyldiamine side-chains, 2, with potent inhibitory activity against Trypanosoma brucei brucei are reported. Compounds 2 showed improved activity and selectivity to T. b. brucei when compared to the lead compound. The most selective compound, 2k, presents a selectivity index value of 6200 and an IC(50) of 10nM against the parasite. These derivatives are also potent inhibitors of the trypanosome papain-like cysteine proteases cruzain, which could, at least in part, explain their antitrypanosomal activity. Overall, these compounds with good antitrypanosomal activity and selectivity provide an encouraging starting point for the rational design of new and effective antitrypanosomal agents.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antiprotozoal Agents / chemical synthesis
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Antiprotozoal Agents / chemistry
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Antiprotozoal Agents / pharmacology*
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Catalytic Domain / drug effects
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Cysteine Proteases / metabolism*
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacology*
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Diamines / chemical synthesis
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Diamines / chemistry
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Diamines / pharmacology*
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Dose-Response Relationship, Drug
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Indole Alkaloids / chemical synthesis
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Indole Alkaloids / chemistry
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Indole Alkaloids / pharmacology*
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Models, Molecular
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Molecular Structure
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Parasitic Sensitivity Tests
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Quinolines / chemical synthesis
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Quinolines / chemistry
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Quinolines / pharmacology*
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Structure-Activity Relationship
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Trypanosoma brucei brucei / drug effects*
Substances
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Antiprotozoal Agents
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Cysteine Proteinase Inhibitors
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Diamines
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Indole Alkaloids
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Quinolines
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cryptolepine
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Cysteine Proteases