Novel pentamidine analogs in the treatment of experimental Pneumocystis carinii pneumonia

Abstract

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...

Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

“…Although these drugs were toxic, they were highly effective in the therapy of pneumocystosis. Many of the diamidine derivatives have been investigated as anti-P. carinii drugs (21,34), but little attention has been paid to the guanylhydrazones. The availability of structure-activity data concerning the effects of guanylhydrazones on trypanosomes (33) should be of help in developing anti-P. carinii drugs.…”

“…Most drug testing has been performed in an immunosuppressed rat model of pneumocystosis, which accurately predicts activity against human P. carinii. Compounds which have exhibited anti-P. carinii activity in the rat model include antifolate drugs (alone or in combination) such as dihydrofolate reductase (DHFR) inhibitors, sulfonamides, sulfones, and sulfonylureas (7, 9, 12, 14, 16-20, 23, 24, 27, 35, 39, 42, 43); sulfonamides in combination with other drugs (e.g., macrolides) (13); diamidines and related cationic compounds (8,11,21,34,40); 8-aminoquinolones, alone or in combination with other agents (1, 28); purine nucleosides (la, 32, 36); polyamine inhibitors (3, 4); nitrofurans (38); 3-glucan inhibitors (26, 29, 30); hydroxynaphthoquinones (14); fluoroquinolones (2); iron chelators (4); and immunological agents (antibodies, cytokines) (10,31).Although the rat model has been very valuable, evaluation of anti-P. carinii drugs is time-consuming, expensive, and labor intensive; only a few compounds can be tested in a given experiment. Treatment studies have been performed by different experimental protocols and methods of evaluating drug efficacy; this lack of standardization has prevented the results of one investigator from being compared directly with those of another.…”

“…Most drug testing has been performed in an immunosuppressed rat model of pneumocystosis, which accurately predicts activity against human P. carinii. Compounds which have exhibited anti-P. carinii activity in the rat model include antifolate drugs (alone or in combination) such as dihydrofolate reductase (DHFR) inhibitors, sulfonamides, sulfones, and sulfonylureas (7, 9, 12, 14, 16-20, 23, 24, 27, 35, 39, 42, 43); sulfonamides in combination with other drugs (e.g., macrolides) (13); diamidines and related cationic compounds (8,11,21,34,40); 8-aminoquinolones, alone or in combination with other agents (1,28); purine nucleosides (la, 32, 36); polyamine inhibitors (3,4); nitrofurans (38); 3-glucan inhibitors (26,29,30); hydroxynaphthoquinones (14); fluoroquinolones (2); iron chelators (4); and immunological agents (antibodies, cytokines) (10,31).…”

Activity of pentamidine and pentamidine analogs against Toxoplasma gondii in cell cultures

“…Pentamidine and its analogs have been shown to have a broad spectrum of activity against intracellular and extracellular protozoan parasites as well as Pneumocystis carinii (2,11,12,(18)(19)(20). Because of this demonstrated effectiveness against parasitic protozoa, we examined the capabilities of pentamidine and nine of its analogs to inhibit replication of the highly pathogenic RH isolate of T. gondii in cell cultures.…”

Anti-Pneumocystis carinii pneumonia activity of dicationic 2,4-diarylpyrimidines

“…Pentamidine and its analogs [19], dicationic bis-benzimidazoles [20,21], and more recently dicationic 2,5-diarylfurans [13] (the latter give calculated radius of curvature values of approximately 15 Å) have been shown to be effective in treating Pneumocystis carinii pneumonia (PCP) and topoisomerase II inhibition may be involved in their mode of action. Collectively, these observations led us to evaluate dicationic 2,4-diarylpyrimidines, which give radius of curvature values in the range predicted to be effective DNA binding agents [17] and which have been demonstrated to strongly bind to AT-rich DNA [14], for effectiveness against PCP.…”