The antiprotozoal compound 1,5-di(4-amidinophenoxy)pentane (pentamidine) and 36 of its analogs were screened for in vitro activity against Leishmania mexicana amazonensis clone 669 C4S (MHOM/BR/73/M2269) and Plasmodium falciparum clones W2 (Indochina HI/CDC) and D6 (Sierra Leone I/CDC). Pentamidine and each of the analogs tested exhibited activity in vitro against L. m. amazonensis and P. falciparum. The pentamidine analogs were more effective against the P. falciparum clones than against L. m. amazonensis. P. falciparum was extremely susceptible to these compounds, with 50% inhibitory concentrations as low as 0.03 FpM. While none of the analogs exhibited marked improvement in antileishmanial activity compared with pentamidine, 12 of the pentamidine analogs showed activity approximately equal to or greater than that of the parent compound. From the promising activity exhibited by the pentamidine analogs in this in vitro study and their potential for reduced toxicity relative to the parent drug, pentamidine-related compounds hold promise as new agents for the treatment of protozoal infections.The efficacy of aromatic diamidines in the treatment of protozoal diseases was first recognized in the 1930s by investigators searching for agents with therapeutic activity against African trypanosomiasis (14). Early clinical trials examining the activities of pentamidine, propamidine, and stilbamidine revealed that these and other aromatic diamidines are effective against the early stages of African trypanosomiasis (6,7,13,14) and against leishmaniasis (11,15,22). Although they are not clinically used in the treatment of malaria, the antiplasmodial activity of aromatic diamidines in monkeys infected with Plasmodium knowlesi was demonstrated during the 1940s (1, 4).Aromatic diamidines not only have antiprotozoal activity but also exhibit activity against bacteria (3), fungi (3), viruses (21), and tumors (12). In the past, their use has mainly been confined to the treatment of protozoal diseases, for which they were first developed. Pentamidine continues to be used in the treatment of the Gambian form of African trypanosomiasis and against antimony-resistant leishmaniasis (17). Pentamidine was first shown to be active against the opportunistic pathogen Pneumocystis carinii in 1958 (10), and in the United States, this compound is primarily used to treat P. carinii pneumonia in patients with the acquired immune deficiency syndrome. The toxicity and side effects associated with the use of pentamidine in the treatment of P. carinii pneumonia in acquired immune deficiency syndrome patients have led to extensive investigations to identify a derivative of pentamidine which is more active against P. carinii pneumonia and less toxic than the parent drug.To this end, over 50 analogs of pentamidine have been synthesized in our laboratory and have been examined for in vivo efficacy against P. carinii in the rat model of disease (10a, 18, 19). The design of more-potent analogs of pentamidine against P. carinii pneumonia has been hampered ...

We have recently demonstrated that substitution of imidazoline moieties for the amidine groups of pentamidine produces a molecule that is effective against rat Pneumocystis carinii pneumonia and that is apparently less toxic than pentamidine. For this reason, 10 novel imidazoline substituted compounds were evaluated for their effect against rat P. carinii pneumonia. While was observed with the drug at any of the dose levels or by either of the routes of administration. However, the low solubility of the drug prevented testing at higher i.v. doses. Our conclusion is that DIMP has the potential of providing a safer and more effective alternative to pentamidine for the treatment of P. carinii pneumonia.Since the 1930s the aromatic diamidine compound pentamidine has been known to be an effective agent for the treatment of parasitic infections (6, 8). Although it was first discovered to be efficacious against Pneumocystis carinji pneumonia in 1958 (4), numerous side effects limited the use of the drug against P. carinii pneumonia prior to the acquired immunodeficiency syndrome (AIDS) epidemic. Because trimethoprim-sulfamethoxazole, the drug of choice for use in patients with P. carinii pneumonia not associated with AIDS, was found to cause a high frequency of adverse reactions in the treatment of AIDS-related disease (3, 5), a sharp increase was seen in the reliance on pentamidine for P. carinii pneumonia therapy. Recent studies have shown that the toxic side effects can be greatly decreased if the drug is given by aerosol administration (7). Despite these encouraging developments, there is still an urgent need for an effective and nontoxic alternative drug that can be administered per os or by the parental route for the treatment of P. carinii pneumonia associated with AIDS. Recent observations by ourselves (8a) and others (10) demonstrated that replacement of the amidine groups of pentamidine analogs with imidazoline moieties results in compounds with increased anti-P. carinii pneumonia activity and reduced toxicity. This discovery provided guidance in the search for new anti-P. carinii pneumonia agents.In the work described here, our on-going screening studies for new therapeutic compounds against P. carinii pneumonia (8a, 9) have been extended to include a series of 10 novel imidazoline-substituted compounds. These compounds were examined for their ability to reduce the mean histologic lung scores in P. carinii-infected rats when the compounds were administered intravenously (i.v.). Two compounds chosen * Corresponding author.from this study and a promising new derivative of pentamidine (butamidine) taken from a previous screening study (8a) were examined for their effects against P. carinii pneumonia in dose-response experiments. In addition, two compounds were tested for their therapeutic effects against P. carinii pneumonia when administration of the drug was per os.MATERIALS AND METHODS Pentamidine analogs. All of the compounds tested in this study were synthesized as the mono-or dihydrochloride salts in ou...

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