A series of bis(amidinobenzimidazoles) and bis(amidinoindoles) with varied linking chains connecting the aromatic groups and various modifications to the basic amidino groups have been prepared. The calf thymus (CT) DNA and nucleic acid homopolymer [poly(dA).poly(dT),poly(dA-dT).poly-(dA-dT), and poly(dG-dC).poly(dG-dC)] binding properties of these compounds have been studied by thermal denaturation (delta Tm) and viscosity. The compounds show a greater affinity for poly(dA).poly(dT) and poly(dA-dT).poly(dA-dT) than for poly(dG-dC).poly(dG-dC). Viscometric titrations indicate that the compounds do not bind by intercalation. Molecular modeling studies and the biophysical data suggest that the molecules bind to the minor groove of CT DNA and homopolymers. Analysis of the shape of the molecules is consistent with this mode of nucleic acid binding. Compounds with an even number of methylenes connecting the benzimidazole rings have a higher affinity for DNA than those with an odd number of methylenes. Molecular modeling calculations that determine the radius of curvature of four defined groups in the molecule show that the shape of the molecule, as a function of chain length, affects the strength of nucleic acid binding. Electronic effects from cationic substituents as well as hydrogen bonding from the imidazole nitrogens also contribute to the nucleic acid affinity. The bis(amidinoindoles) show no structurally associated differential in nucleic acid base pair specificity or affinity.

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On the basis of a previously observed correlation between the antimicrobial activity and DNA binding strength of dicationic molecules, a series of 10 dicationically substituted bis-benzimidazoles were tested for activity in the rat model of Pneumocystis carinii pneumonia. One of the compounds, 1,4-bis[5-(2-imidazolinyl)-2-benzimidazolyl]butane, was found to be more potent and less toxic than pentamidine.

Nine dicationically substituted bis-benzimidazoles were examined for their in vitro activities against Giardia lamblia WB (ATCC 30957). The potential mechanisms of action of these compounds were evaluated by investigating the relationship among in vitro antigiardial activity and the affinity of the molecules for DNA and their ability to inhibit the activity of giardial topoisomerase II. Each compound demonstrated antigiardial activity, as measured by assessing the incorporation of [methyl-3H]thymidine by giardial trophozoites exposed to the test agents. Three compounds exhibited excellent in vitro antigiardial activities, with 50%o inhibitory concentrations which compared very favorably with those of two currently used drugs, quinacrine HCI and metronidazole. Putative mechanisms of action for these compounds were suggested by the strong correlation observed among in vitro antigiardial activity and the affinity of the molecules for natural and synthetic DNA and their ability to inhibit the relaxation activity of giardial topoisomerase II. A strong correlation between the DNA binding affinity of these compounds and their inhibition of giardial topoisomerase II activity was also observed.Giardia lamblia is a common cause of endemic and epidemic diarrheal disease throughout the world. Some individuals harbor asymptomatic infections, while others may exhibit acute or chronic gastrointestinal disease. Four agents are presently used to treat giardiasis: the nitroimidazoles metronidazole and tinidazole, the nitrofuran furazolidone, and quinacrine HCl, an acridine. Many problems are associated with the currently used chemotherapeutic agents, including treatment failures, unpleasant side effects, activity against normal intestinal flora, and possible carcinogenicity. While treatment of symptomatic individuals is recommended, there is controversy as to whether asymptomatic cyst passers should be treated, especially in light of the problems associated with the antigiardial agents presently available. More-effective and less-toxic agents are therefore needed for the treatment of giardiasis.The search for new antigiardial agents has been aided by improvements in axenic culturing of the organism (13) and drug susceptibility testing (3,12). Among the classes of compounds recently examined for antigiardial activity are anthelminthic benzimidazoles (1,8,14,15) Washington, DC 20307. which are used at present to treat the infection (2). In addition, there was a strong correlation between the antigiardial activities of the pentamidine analogs and their affinity for calf thymus DNA and poly(dA) poly(dT). The ability of pentamidine to bind to DNA has been proposed as a mechanism of action for this and related compounds. Pentamidine and related molecules have also been identified as potential inhibitors of the activity of type II topoisomerases (7,17).A number of dicationically substituted bis-benzimidazoles, originally developed as protease inhibitors and DNA binding agents, were available in our laboratory for in vitro antimi...