A new, orally-active inhibitor of dihydrofolic acid reductase (DHFR), PS- 1 5 (N-(3-(2,4,5-trichlorophenoxy)propyloxy)-N'-(1-methylethyl)-imidocarbonimidicdiamide hydrochloride), has significant activity against drug-resistant Plasmodium falciparum. It is not cross-resistant with other inhibitors of DHFR (e.g., pyrimethamine and cycloguanil). Although it bears similarities to proguanil, PS-15 represents a new antifolate class of drugs that we have named oxyguanils or hydroxylamine-derived biguanides. This compound displays intrinsic antimalarial activity and also is metabolized in vivo to WR99210, an extremely active triazine inhibitor of DHFR. When tested in vitro against drug-resistant clones of P. falciparum, PS-15 was more active than proguanil, and the putative metabolite, WR99210, was more active than the proguanil metabolite cycloguanil. The drug is also more active as well as less toxic than proguanil when administered orally to mice infected with P. berghei. When administered orally to Aotus monkeys infected with multidrug-resistant P. falciparum, PS-15 was more active than either proguanil or WR99210. In 1973, WR99210 underwent clinical trials for safety and tolerance in volunteers. The trials showed gastrointestinal intolerance and limited bioavailability; further development of the drug was abandoned. Because PS-15 has intrinsic antimalarial activity, is not cross-resistant with other DHFR inhibitors, and can be metabolized to WR99210 in vivo, oral administration of this new drug should circumvent the shortcomings and retain the advantages found with both proguanil and WR99210.
