In vitro and in vivo activities of aminoadamantane and aminoalkylcyclohexane derivatives against Trypanosoma brucei


Kelly, JM; Quack, G; Miles, MM; (2001) In vitro and in vivo activities of aminoadamantane and aminoalkylcyclohexane derivatives against Trypanosoma brucei. Antimicrobial agents and chemotherapy, 45 (5). pp. 1360-6. ISSN 0066-4804 DOI: 10.1128/AAC.45.5.1360-1366.2001

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Abstract

We reported recently that the bloodstream form of the African trypanosome, Trypanosoma brucei, is sensitive to the anti-influenza virus drug rimantadine. In the present report we describe the trypanocidal properties of a further 62 aminoadamantane and aminoalkylcyclohexane derivatives. Seventeen of the compounds were found to be more active than rimantadine, with four inhibiting growth in vitro of T. brucei by >90% at concentrations of 1 microM. The most active derivative (1-adamantyl-4-amino-cyclohexane) was about 20 to 25 times more effective than rimantadine. We observed a correlation between structural features of the derivatives and their trypanocidal properties; hydrophobic substitutions to the adamantane or cyclohexane rings generally enhanced activity. As with rimantadine, the activity in vitro varied with the pH. T. brucei was more sensitive in an alkaline environment (including a normal bloodstream pH of 7.4) and less sensitive under acidic conditions. Tests for activity in vivo were carried out with a mouse model of infection with a virulent strain of T. brucei. Although the parasitemia was not eliminated, it could be transiently suppressed by >98% with the most active compounds tested. These results suggest that aminoadamantane derivatives could have potential as a new class of trypanocidal agents.

Item Type: Article
Keywords: Adamantane/*analogs & derivatives/chemistry/pharmacology/therapeutic use, Animal, Cyclohexylamines/chemistry/*pharmacology/therapeutic use, Disease Models, Animal, Drug Evaluation, Preclinical, Human, Hydrogen-Ion Concentration, Mice, Structure-Activity Relationship, Support, Non-U.S. Gov't, Trypanocidal Agents/chemistry/*pharmacology/therapeutic use, Trypanosoma brucei brucei/*drug effects/growth & development, Trypanosomiasis/drug therapy, Adamantane, analogs & derivatives, chemistry, pharmacology, therapeutic use, Animal, Cyclohexylamines, chemistry, pharmacology, therapeutic use, Disease Models, Animal, Drug Evaluation, Preclinical, Human, Hydrogen-Ion Concentration, Mice, Structure-Activity Relationship, Support, Non-U.S. Gov't, Trypanocidal Agents, chemistry, pharmacology, therapeutic use, Trypanosoma brucei brucei, drug effects, growth & development, Trypanosomiasis, drug therapy
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Research Centre: Antimicrobial Resistance Centre (AMR)
PubMed ID: 11302796
Web of Science ID: 168240300007
URI: http://researchonline.lshtm.ac.uk/id/eprint/16244

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