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

We reported recently that the bloodstream form of the African trypanosome, Trypanosoma brucei, is sensitive to the anti-influenza virus drug rimantadi ne. in the present report we describe the trypanocidal properties of a furt her 62 aminoadamantane and aminoalkylcyclohexane derivatives. Seventeen of the compounds were found to be more active than rimantadine, with four inhi biting growth in vitro of T, brucei by > 90% at concentrations of 1 muM. Th e 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 t he 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 elim inated, it could be transiently suppressed by > 98% with the most active co mpounds tested. These results suggest that aminoadamantane derivatives coul d have potential as a new class of trypanocidal agents.