CHARACTERIZATION OF THE POTENT IN-VITRO AND IN-VIVO ANTIMALARIAL ACTIVITIES OF IONOPHORE COMPOUNDS

Large-scale in vitro screening of different types of ionophores previo usly pinpointed nine compounds that were very active and selective in vitro against Plasmodium falciparum; their in vitro and in vivo antima larial effects were further studied, Addition of the ionophores to syn chronized P, falciparum suspensions revealed that all P, falciparum st ages were sensitive to the drugs, However, the schizont stages were th ree- to ninefold more sensitive, and 12 h was required for complete pa rasite clearance, Pretreatment of healthy erythrocytes with toxic dose s of ionophores for 24 to 48 h showed that the activity was not due to an irreversible effect on the host erythrocyte, No preferential ionop hore adsorption in infected or uninfected erythrocytes occurred, On th e other hand, ionophore molecules strongly bound to serum proteins sin ce increasing the serum concentration from 2 to 50% led to almost a 25 -fold parallel increase in the ionophore 50% inhibitory concentration, Mice infected ,vith the malaria parasites Plasmodium vinckei petteri or Plasmodium chabaudi were successfully treated with eight ionophores in a 4-day suppressive test, The 50% effective dose after intraperito neal administration ranged from 0.4 to 4.1 mg/kg of body weight, and t he therapeutic indices were about 5 for all ionophores except monensin A methyl ether, 5-bromo lasalocid A, and gramicidin D, whose therapeu tic indices were 12, 18, and 344, respectively, These three compounds were found to be curative, with no recrudescence, Gramicidin D, which presented impressive antimalarial activity, requires parenteral admini stration, while 5-bromo lasalocid A has the major advantage of being a ctive after oral administration, Overall, the acceptable levels of tox icity and the good in vivo therapeutic indices in the rodent model hig hlight the interesting potential of these ionophores for the treatment of malaria in higher animals.