Activity of cationically substituted bis-benzimidazoles against experimental Pneumocystis carinii pneumonia

Tidwell, R. R.; Jones, S. K.; Naiman, Noreen; Berger, Louise C.; Brake, W B; Dykstra, Christine C.; Hall, James Edwin

doi:10.1128/aac.37.8.1713

Cited by 88 publications

(79 citation statements)

References 19 publications

(19 reference statements)

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“…As expected, the monocation 15 does not effectively interact with DNA and it shows no activity against PCP in the immunosuppressed rat model. Compound 8 exhibits the strongest interaction with DNA in this series; analogous results have been noted for the tetrahydropyrimidine cationic center in other similar series of dicationic molcules [20,21]. There is no apparent direct relationship between topoisomerase II inhibition, modeled using the enzyme from Gardia lamblia, and DNA binding or in vivo anti-PCP activity.…”

Section: Biological Results and Discussionsupporting

confidence: 64%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Kumar

Wilson

et al. 1996

European Journal of Medicinal Chemistry

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Summary-A synthesis of 2,4-bis-(4-amidinophenyl)pyrimidine 6, 2,4-bis-[(4-imidazolin-2-yl)phenyl)]pyrimidine 7, 2,4-bis[(4-tetrahydropyrimidinyl-2-yl)phenyl]pyrimidine 8, 2,4-bis Compounds 6, 9-11, and 20 given at 5 mg/kg are more active and less toxic than pentamidine at its effective dose when evaluated against Pneumocystis carinii pneumonia (PCP) in the immunosuppressed rat model. Several compounds in this series are being evaluated further as potential new anti-PCP agents.

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Section: Biological Results and Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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

Kumar

Wilson

et al. 1996

European Journal of Medicinal Chemistry

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“…The ratio was at least 40 for topoisomerase I and 80 for topoisomerase II. It is worth noting that compound 8 was among the most effective compounds in the treatment of PCP in the rat model (41). DISCUSSION The current work originated with studies on pentamidine analogs that clearly showed a correlation between DNA minor groove-binding strength and antiparasitic activity (3).…”

Section: Resultsmentioning

confidence: 99%

Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells

Dykstra

McClernon

Elwell

et al. 1994

Antimicrob Agents Chemother

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Type I and II topoisomerase activities were partially purified from Pneumocystis carinii. The catalytic (strand-passing) activities of both enzymes were selectively inhibited by members of a series of dicationicsubstituted bis-benzimidazoles compared with those of topoisomerases of mammalian (calf thymus) origin.The most active inhibitors of the parasite enzymes were also highly effective in an in vivo animal model of P.carinii pneumonia. Selected dicationic-substituted bis-benzimidazoles also strongly inhibited the induction of the topoisomerase I-and 11-mediated cleavable complex, suggesting that the biologically active DNA minor groove-binding molecules inhibit the enzyme-DNA binding step of the topoisomerase reaction sequence. The apparent selectivities for the parasite enzymes and the low levels of toxicity to mammalian cells for the biologically active bis-benzimidazoles suggest that these compounds hold promise as effective therapeutic agents in the treatment of a life-threatening AIDS-related disease, P. carinii pneumonia.Dicationic-substituted aromatic molecules related to pentamidine have long been known to be effective antiparasitic agents (35). Recent studies have found that a number of direct analogs of pentamidine have activity against Pneumocystis carinii (19), Giardia lamblia (3), Toxoplasma gondii (25), Cryptosporidium parvum (7), Leishmania amazonensis subsp. mexicana (5), and Plasmodium falciparum (5). A strong correlation was observed between compound activity against G. lamblia in vitro and DNA-binding ability (3). On the basis of those initial results, studies of antiparasitic compounds were extended to a series of compounds with much stronger DNA-binding affinities, the dicationic bis-benzimidazoles. As observed with the pentamidine analogs, a strong correlation was found between DNA binding strength and antigiardial activity for the bisbenzimidazole series [r2 = 0.96 versus calf thymus DNA and i2 = 0.97 versus poly(dA) * (dT)](4). Other studies confirmed that the effective antigiardial compounds were strong DNA minor groove-binding agents with an AT base pair preference (14). Molecular modeling calculations in that study showed that the DNA-binding strength for this class of compound depended on the radius of curvature on the basis of four defined moieties within the molecules, the distance between cationic moieties, the electronic effects from cationic substituents, and hydrogen bonding. There was no evidence of either an intercalative or a covalent interaction of these compounds with nucleic acids. The antigiardiasis study also revealed a convincing correlation between antitopoisomerase II activity and in vitro activity against G. lamblia for the dicationic bis-benzimidazoles (r2 = 0.91) (4). It is unclear whether these compounds manifest their antiparasitic activity primarily by binding to DNA, topoisomerase, or the enzyme-DNA binary complex.As part of a continuing investigation to determine the mechanism of the anti-P. carinii action of these dicationic molecules and to develop new ag...

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“…A P. cariniiinfected rat model has been widely used for examining the efficacy of experimental drugs (3,8,16,19,20). Although this system produces P. carinii pneumonia in immunosuppressed rats 10 weeks earlier than our system, dexamethazone and antibiotics have to be used concomitantly throughout the study.…”

Section: Discussionmentioning

confidence: 99%

Successful treatment of Pneumocystis carinii Pneumonia in mice with benanomicin A (ME1451)

Yasuoka

Oka

Komuro

et al. 1995

Antimicrob Agents Chemother

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Benanomicin A (BNM-A) has antimycotic activities via binding to mannan in the cell walls of fungi. Anti-Pneumocystis carinii activity of the agent was examined in the P. carinii-infected BALB/c nu/nu female mouse model because P. carinii also possesses mannan in the membranes. The infected mice were treated with intraperitoneal injections of six doses of BNM-A (1, 2.5, 5, 10, 30, and 100 mg/kg of body weight), 4 mg of pentamidine isethionate per kg, 100 mg of sulfamethoxazole per kg combined with 20 mg of trimethoprim per kg (co-trimoxazole), or saline for 21 days. Each dosage group consisted of 10 mice. During treatment, five mice in the control group (saline) died, whereas 8 to 10 mice in all treatment groups survived. Almost the same efficacies were obtained for the groups treated with 5 mg or more and 10 mg or more of BNM-A per kg regarding the weight and number, respectively, of cysts found in the lungs as were obtained for the groups treated with pentamidine isethionate and co-trimoxazole. Overall, a dose of 10 mg of BNM-A per kg was effective against P. carinii pneumonia infection in the mice. Thus, BNM-A is a good candidate for a novel treatment for P. carinii pneumonia as a compound with a new mechanism of action against P. carinii.

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Activity of cationically substituted bis-benzimidazoles against experimental Pneumocystis carinii pneumonia

Cited by 88 publications

References 19 publications

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

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

Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells

Successful treatment of Pneumocystis carinii Pneumonia in mice with benanomicin A (ME1451)

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