EFFECTS OF STEROIDAL ALLENIC PHOSPHONIC ACID-DERIVATIVES ON THE PARASITIC PROTISTS LEISHMANIA-DONOVANI, LEISHMANIA-MEXICANA MEXICANA, AND PNEUMOCYSTIS-CARINII CARINII

Several pathogenic fungi and protozoa are known to have sterols distin ct from those of their mammalian hosts, Of particular interest as targ ets for drug development are the biosyntheses of the sterols of import ant parasites such as the kinetoplastid flagellates and the AIDS-assoc iated opportunistic protist Pneumocystis carinii. These pathogens synt hesize sterols with an alkyl group at C-24, and some have a double bon d at C-22 of the side chain, Humans and other mammalian hosts are inca pable of C-24 alkylation and C-22 desaturation. In the present study, three steroidal compounds with side chains substituted by phosphonyl-l inked groups were synthesized and tested for their effects on Leishman ia donovani and L. mexicana mexicana culture growth. The compounds inh ibited organism proliferation at concentrations in micrograms per mill iliter, The most potent inhibitors of this group of compounds were cha racterized by two ethyl groups at the phosphate function, Leishmania o rganisms treated with o)ethylidienyl]3-methoxy-19-norpregna-1,3,5-trie ne exhibited reduced growth after transfer into inhibitor-free medium. Because there are currently no axenic methods available for the conti nuous subcultivation of P. carinii, the effects of these drugs on this organism were evaluated by two alternative screening methods, The sam e two diethyl phosphonosteroid compounds that inhibited Leishmania pro liferation were also the most active against P. carinii as determined by the potent effect they had on reducing cellular ATP content, Cystic as well as trophic for,ms responded to the drug treatments, as evalua ted by a dual fluorescent staining live-dead assay, Other modification s of steroidal phosphonates may lead to the development of related dru gs with increased activity and specificity for the pathogens.