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. 1993 Dec;37(12):2668–2673. doi: 10.1128/aac.37.12.2668

Structure-activity studies of dicationically substituted bis-benzimidazoles against Giardia lamblia: correlation of antigiardial activity with DNA binding affinity and giardial topoisomerase II inhibition.

C A Bell 1, C C Dykstra 1, N A Naiman 1, M Cory 1, T A Fairley 1, R R Tidwell 1
PMCID: PMC192773  PMID: 8109934

Abstract

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% inhibitory concentrations which compared very favorably with those of two currently used drugs, quinacrine HCl 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.

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Selected References

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  1. Bell C. A., Cory M., Fairley T. A., Hall J. E., Tidwell R. R. Structure-activity relationships of pentamidine analogs against Giardia lamblia and correlation of antigiardial activity with DNA-binding affinity. Antimicrob Agents Chemother. 1991 Jun;35(6):1099–1107. doi: 10.1128/aac.35.6.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boreham P. F., Phillips R. E., Shepherd R. W. The sensitivity of Giardia intestinalis to drugs in vitro. J Antimicrob Chemother. 1984 Nov;14(5):449–461. doi: 10.1093/jac/14.5.449. [DOI] [PubMed] [Google Scholar]
  3. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  4. Cory M., Tidwell R. R., Fairley T. A. Structure and DNA binding activity of analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) J Med Chem. 1992 Feb 7;35(3):431–438. doi: 10.1021/jm00081a003. [DOI] [PubMed] [Google Scholar]
  5. Douc-Rasy S., Kayser A., Riou J. F., Riou G. ATP-independent type II topoisomerase from trypanosomes. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7152–7156. doi: 10.1073/pnas.83.19.7152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Edlind T. D., Hang T. L., Chakraborty P. R. Activity of the anthelmintic benzimidazoles against Giardia lamblia in vitro. J Infect Dis. 1990 Dec;162(6):1408–1411. doi: 10.1093/infdis/162.6.1408. [DOI] [PubMed] [Google Scholar]
  7. Fairley T. A., Tidwell R. R., Donkor I., Naiman N. A., Ohemeng K. A., Lombardy R. J., Bentley J. A., Cory M. Structure, DNA minor groove binding, and base pair specificity of alkyl- and aryl-linked bis(amidinobenzimidazoles) and bis(amidinoindoles). J Med Chem. 1993 Jun 11;36(12):1746–1753. doi: 10.1021/jm00064a008. [DOI] [PubMed] [Google Scholar]
  8. Farthing M. J., Pereira M. E., Keusch G. T. Giardia lamblia: evaluation of roller bottle cultivation. Exp Parasitol. 1982 Dec;54(3):410–415. doi: 10.1016/0014-4894(82)90050-9. [DOI] [PubMed] [Google Scholar]
  9. Geratz J. D., Tidwell R. R., Schwab J. H., Anderle S. K., Pryzwansky K. B. Sequential events in the pathogenesis of streptococcal cell wall-induced arthritis and their modulation by bis(5-amidino-2-benzimidazolyl)methane (BABIM). Am J Pathol. 1990 Apr;136(4):909–921. [PMC free article] [PubMed] [Google Scholar]
  10. Inge P. M., Farthing M. J. A radiometric assay for antigiardial drugs. Trans R Soc Trop Med Hyg. 1987;81(2):345–347. doi: 10.1016/0035-9203(87)90260-4. [DOI] [PubMed] [Google Scholar]
  11. Keister D. B. Axenic culture of Giardia lamblia in TYI-S-33 medium supplemented with bile. Trans R Soc Trop Med Hyg. 1983;77(4):487–488. doi: 10.1016/0035-9203(83)90120-7. [DOI] [PubMed] [Google Scholar]
  12. Meloni B. P., Thompson R. C., Reynoldson J. A., Seville P. Albendazole: a more effective antigiardial agent in vitro than metronidazole or tinidazole. Trans R Soc Trop Med Hyg. 1990 May-Jun;84(3):375–379. doi: 10.1016/0035-9203(90)90324-8. [DOI] [PubMed] [Google Scholar]
  13. Reynoldson J. A., Thompson R. C., Meloni B. P. In vivo efficacy of albendazole against Giardia duodenalis in mice. Parasitol Res. 1991;77(4):325–328. doi: 10.1007/BF00930909. [DOI] [PubMed] [Google Scholar]
  14. Shapiro T. A., Englund P. T. Selective cleavage of kinetoplast DNA minicircles promoted by antitrypanosomal drugs. Proc Natl Acad Sci U S A. 1990 Feb;87(3):950–954. doi: 10.1073/pnas.87.3.950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Tidwell R. R., Geratz J. D., Dann O., Volz G., Zeh D., Loewe H. Diarylamidine derivatives with one or both of the aryl moieties consisting of an indole or indole-like ring. Inhibitors of arginine-specific esteroproteases. J Med Chem. 1978 Jul;21(7):613–623. doi: 10.1021/jm00205a005. [DOI] [PubMed] [Google Scholar]
  16. Tidwell R. R., Geratz J. D., Dubovi E. J. Aromatic amidines: comparison of their ability to block respiratory syncytial virus induced cell fusion and to inhibit plasmin, urokinase, thrombin, and trypsin. J Med Chem. 1983 Feb;26(2):294–298. doi: 10.1021/jm00356a036. [DOI] [PubMed] [Google Scholar]
  17. Tidwell R. R., Jones S. K., Naiman N. A., Berger L. C., Brake W. B., Dykstra C. C., Hall J. E. Activity of cationically substituted bis-benzimidazoles against experimental Pneumocystis carinii pneumonia. Antimicrob Agents Chemother. 1993 Aug;37(8):1713–1716. doi: 10.1128/aac.37.8.1713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. al-Waili N. S., al-Waili B. H., Saloom K. Y. Therapeutic use of mebendazole in giardial infections. Trans R Soc Trop Med Hyg. 1988;82(3):438–438. doi: 10.1016/0035-9203(88)90156-3. [DOI] [PubMed] [Google Scholar]

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