ANTIPNEUMOCYSTIS ACTIVITIES OF AROMATIC DIAMIDOXIME PRODRUGS

Aromatic dicationic compounds, such as pentamidine, have potent antimi crobial activities. Clinical use of these compounds' has been restrict ed, however, by their toxicity and limited oral activity. A novel appr oach, using amidoxime derivatives as prodrugs, has recently been propo sed to overcome these limitation. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Ni ne novel amidoxime derivatives were synthesized and tested in the pres ent study for activity against Pneumocystis carinii in corticosteroid- suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct;pentamidine analogs had excellent oral and intravenous activit ies and reduced acute host toxicity. These compounds are not likely ca ndidates for future drug development, however because they have chroni c toxic;effects and the active amidine compounds have multiple sites s usceptible to oxidative metabolism, which complicates their pharmacolo gy and toxicology. Novel diamidoximes from three other structural clas ses, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even thou gh the corresponding diamidines were very active intravenously. Both a ctive and inactive amidoximes were readily metabolized to the correspo nding amidines by cell-free liver homogenates. Thus, the amidoxime pro drug approach may provide a strategy to exploit the potent antimicrobi al and other pharmacological activities of selected, but certainly not all, aromatic diamidines.