A series of 33 analogues of the anti-Pneumocystis carinii drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) was synthesized for screening against a rat model of P. carinii pneumonia (PCP). Twenty-five of the compounds showed efficacy against PCP when compared to a saline-treated control group. Two compounds, 1,4-bis(4-amidinophenoxy)butane (butamidine, 6) and 1,3-bis(4-amidino-2-methoxyphenoxy)propane (DAMP, 16), were statistically more effective than the parent drug in treating PCP in the rat model of infection. In addition to their activity against PCP, the compounds were also evaluated for antitrypsin activity, ability to inhibit thymidylate synthetase, affinity for DNA, and toxicity. No correlation was observed between the tested molecular interactions of the diamidines and their effectiveness against PCP.

A series of 62 diarylamidine derivatives was evaluated for their antiproteolytic activity. In all but two of the compounds one or both of the amidino-substituted aryl moieties was either an indole or an indole-like ring. The latter included indene, benzimidazole, benzofuran, benzol[beta]thiophene, and several other related nitrogen-containing heterocycles. Several of the compounds exhibited considerable inhibitory potency against thrombin, trypsin, and pancreatic kallikrein. An outstanding inhibitor of trypsin was found in bis(5-amidino-2-benzimidazolyl)methane (compound 42) with a Ki value of 1.7 X 10(-8) M(pH. 8.1, 37 degrees C). Another derivative, 1,2-di(4-amidino-2-benzofuranyl)ethane (compound 21), proved to be a highly effective inhibitor of the overall blood clotting process. From a general structure-activity standpoint these compounds demonstrate that minor structural variations of low-molecular-weight inhibitors can result in significant changes in specificity and potency with regard to antiproteolytic activity.

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...

In a model for virus-induced myocarditis and congestive heart failure, rabbit coronavirus infection was divided into acute (days 2-5) and subacute (days 6-12) phases on the basis of day of death and pathologic findings. During the acute phase, the principal histologic lesions were degeneration and necrosis of myocytes, myocytolysis, interstitial edema, and hemorrhage. The severity of these changes increased in the subacute phase. Pleural effusion and congestion of the lungs and liver were also present at this time. Myocarditis was detected by day 9 and peaked by day 12. Heart weights and heart weight-to-body weight ratios were increased, and dilation of the right ventricular cavity became prominent early in infection and persisted. In contrast, dilation of the left ventricle occurred late in the subacute stage. Virus was isolated from infected hearts between days 2 and 12. These data suggest that rabbit coronavirus infection progresses to myocarditis and congestive heart failure.

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