LYMPHOTROPIC ANTIFILARIAL AGENTS DERIVED FROM CLOSANTEL AND CHLORAMBUCIL

New closantel and chlorambucil prodrugs expected to accumulate in the lymphatic system were evaluated on the filaria Molinema dessetae, The prodrugs of closantel had a delayed effect in vitro on the infective l arvae compared to the free drug. The closantel prodrugs were less toxi c in vivo than closantel itself. The most active prodrug after treatme nt at 200 mu mol/kg by the oral route was the 1,3-dipalmitoyl-2-succin yl-glycerol-closantel. The macro-filaricidal delayed effect of closant el prodrugs was of interest to prevent anaphylactic shock. In vitro ch lorambucil was active on M. dessetae infective larvae with an IC50 of 26 mu M. 1,3-Dipalmitoyl-2-chlorambucil-glycerol was slightly active w hile the addition of a thioether function between the drug and the lym photropic ligand canceled the activity. However, no activity with chlo rambucil and its prodrugs was observed in vivo. The lymphotropism of t hese prodrugs has now to be verified using comparative pharmacokinetic s in serum and lymph to quantify the increase in drug concentration in lymph. (C) 1997 Australian Society for Parasitology. Published by Els evier Science Ltd.