Abstract
Eight dicationic compounds related to pentamidine were studied for trypanocidal activity in seven trypanosome isolates. In vitro studies revealed that diamidines are more potent than diimidazolines. For example, 2 (a diamidine) and 4 (a diimidazoline) inhibited the growth of KETRI 243 with IC50 values of 2.3 and 900 nM, respectively. Introduction of polar groups into the linker decreased the effectiveness of the compounds against drug-resistant trypanosomes. In compounds with a 2-butene linker between the cationic groups, trans-isomers were more potent than cis-isomers. The cis- and trans-buteneamidines cured infection caused by Trypanosoma brucei brucei (EATRO Lab 110) and protected mice against infection by Trypanosoma brucei rhodesiense isolates, some of which are resistant to diamidines and melarsoprol.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cations, Divalent / chemical synthesis
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Cations, Divalent / chemistry
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Cations, Divalent / pharmacology*
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Cations, Divalent / therapeutic use
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Cattle
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DNA / genetics
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DNA / metabolism
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Drug Design
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Drug Evaluation, Preclinical
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Female
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Inhibitory Concentration 50
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Magnetic Resonance Spectroscopy
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Mice
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Pentamidine / analogs & derivatives*
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Pentamidine / chemical synthesis
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Pentamidine / pharmacology*
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Pentamidine / therapeutic use
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Structure-Activity Relationship
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Thymus Gland
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / chemistry
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Trypanocidal Agents / pharmacology*
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Trypanocidal Agents / therapeutic use
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Trypanosoma brucei brucei / drug effects*
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Trypanosoma brucei rhodesiense / drug effects*
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Trypanosomiasis, African / drug therapy*
Substances
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Cations, Divalent
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Trypanocidal Agents
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Pentamidine
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DNA