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 larvae compared to the free drug. The closantel prodrugs were less toxic in vivo than closantel itself. The most active prodrug after treatment at 200 mumol/kg by the oral route was the 1,3-dipalmitoyl-2-succinyl-glycerol-closantel. The macrofilaricidal delayed effect of closantel prodrugs was of interest to prevent anaphylactic shock. In vitro, chlorambucil was active on M. dessetae infective larvae with an IC50 of 26 microM. 1,3-Dipalmitoyl-2-chlorambucil-glycerol was slightly active while the addition of a thioether function between the drug and the lymphotropic ligand canceled the activity. However, no activity with chlorambucil and its prodrugs was observed in vivo. The lymphotropism of these prodrugs has now to be verified using comparative pharmacokinetics in serum and lymph to quantify the increase in drug concentration in lymph.