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Novel amidines and analogues as promising agents against intracellular parasites: a systematic review

  • M. N. C. SOEIRO (a1), K. WERBOVETZ (a2), D. W. BOYKIN (a3), W. D. WILSON (a3), M. Z. WANG (a4) and A. HEMPHILL (a5)...

Summary

Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.

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Corresponding author

*Corresponding author: Laboratόrio de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. E-mail: soeiro@ioc.fiocruz.br

References

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Alvar, J., Vélez, I. D., Bern, C., Herrero, M., Desjeux, P., Cano, J., Jannin, J. and den Boer, M. (2012). WHO Leishmaniasis control team. Leishmaniasis worldwide and global estimates of its incidence. PLoS One 7, e35671.
Aly, A. A. and Nour-El-Din, A. M. (2008). Functionality of amidines and amidrazones. Archive for Organic Chemistry 153194.
Ando, M., Kamei, R., Komagoe, K., Inoue, T., Yamada, K. and Katsu, T. (2012). In situ potentiometric method to evaluate bacterial outer membrane-permeabilizing ability of drugs: example using antiprotozoal diamidines. Journal of Microbiological Methods 91, 497500.
Ansede, J. H., Voyksner, R. D., Ismail, M. A., Boykin, D. W., Tidwell, R. R. and Hall, J. E. (2005). In vitro metabolism of an orally active O-methyl amidoxime prodrug for the treatment of CNS trypanosomiasis. Xenobiotica 35, 211226.
Arafa, R. K., Brun, R., Wenzler, T., Tanious, F. A., Wilson, W. D., Stephens, C. E. and Boykin, D. W. (2005). Synthesis, DNA affinity, and antiprotozoal activity of fused ring dicationic compounds and their prodrugs. Journal of Medicinal Chemistry 48, 54805488.
Ashley, J. N., Barber, H. J., Ewins, A. J., Newbery, G. and Self, A. D. H. (1942). A chemotherapeutic comparison of the trypanocidal action of some aromatic diamidines. Journal of the Chemical Society, 103116.
Bakunov, S. A., Bakunova, S. M., Ghebru, M., Werbovetz, K. A., Brun, R. and Tidwell, R. R. (2010). Synthesis and antiprotozoal activity of cationic 1,4-diphenyl-1H-1,2,3-triazoles. Journal of Medicinal Chemistry 53, 254272.
Bakunova, S. M., Bakunov, S. A., Wenzler, T., Barscz, T., Werbovetz, K. A., Brun, R., Hall, J. E. and Tidwell, R. R. (2007). Synthesis and in vitro antiprotozoal activity of bisbenzofuran cations. Journal of Medicinal Chemistry 50, 58075823.
Bakunova, S. M., Bakunov, S. A., Wenzler, T., Barszcz, T., Werbovetz, K., Brun, R. and Tidwell, R. R. (2009). Synthesis and antiprotozoal activity of pyridyl analogues of pentamidine. Journal of Medicinal Chemistry 52, 46574667.
Banerjee, M., Farahat, A., Kumar, A., Wenzler, T., Brun, R., Munde, M., Wilson, W., Zhu, X., Werbovetz, K. and Boykin, D. (2012). Synthesis, DNA binding and antileishmanial activity of low molecular weight bis arylimidamides. European Journal of Medicinal Chemistry 55, 449454.
Barratt, J. L., Harkness, J., Marriott, D., Ellis, J. T. and Stark, D. (2010). Importance of no enteric protozoan infections in immunocompromised people. Clinical Microbiology Reviews 23, 795836.
Barrett, M. P., Burchmore, R. J. S., Stich, A., Lazzari, J. O., Frasch, A. C. and Cazzulo, J. J. (2003). The trypanosomiases. Lancet 362, 14691480.
Barrett, M. P., Boykin, D. W., Brun, R. and Tidwell, R. R. (2007). Human African trypanosomiasis: pharmacological re-engagement with a neglected disease. British Journal of Pharmacology 152, 11551171.
Basselin, M., Denise, H., Coombs, G. H. and Barrett, M. P. (2002). Resistance to pentamidine in Leishmania mexicana involves exclusion of the drug from the mitochondrion. Antimicrobial Agents and Chemotherapy 46, 37313738.
Basso, W., Schares, G., Gollnick, N. S., Rütten, M. and Deplazes, P. (2011). Exploring the life cycle of Besnoitia besnoiti – experimental infection of putative definitive and intermediate host species. Veterinary Parasitology 178, 223234.
Batista, D. G. J., Batista, M. M., Oliveira, G. M., Amaral, P. B., Lannes-Vieira, J., Britto, C. C., Junqueira, A., Lima, M. M., Romanha, A. J., Sales Junior, P. A., Stephens, C. E., Boykin, D. W. and Soeiro, M. N. C. (2010 a). Arylimidamide DB766, a potential chemotherapeutic candidate for Chagas' disease treatment. Antimicrobial Agents and Chemotherapy 54, 29402952.
Batista, D. G. J., Pacheco, M. G. O., Kumar, A., Branowska, D., Ismail, M. A., Hu, L., Boykin, D. W. and Soeiro, M. N. C. (2010 b). Biological, ultrastructural effect and subcellular localization of aromatic diamidines in Trypanosoma cruzi. Parasitology 137, 251259.
Batista, D. G. J., Batista, M. M., de Oliveira, G. M., Britto, C. C., Rodrigues, A. C., Stephens, C. E., Boykin, D. W. and Soeiro, M. N. C. (2011). Combined treatment of heterocyclic analogues and benznidazole upon Trypanosoma cruzi in vivo. PLoS One 6, e22155.
Bell, C. A., Hall, J. E., Kyle, D. E., Grogl, M., Ohmeng, K. A., Allen, M. A. and Tidwell, R. R. (1990). Structure-activity relationships of analogs of pentamidine against Plasmodium falciparum and Leishmania mexicana amazonensis. Antimicrobial Agents and Chemotherapy 34, 13811386.
Berger, B. J., Naiman, N. A., Hall, J. E., Peggins, J., Brewer, T. G. and Tidwell, R. R. (1992). Primary and secondary metabolism of pentamidine by rats. Antimicrobial Agents and Chemotherapy 36, 18251831.
Berman, J. and Wyler, D. (1980). An in vitro model for investigation of chemotherapeutic agents in leishmaniasis. Journal of Infectious Diseases 142, 8386.
Blagburn, B. L., Sundemann, C. A., Lindsay, D. S., Hall, J. E. and Tidwell, R. R. (1991). Inhibition of Cryptosporidium parvum in neonatal Hsd:(ICR)BR Swiss mice by polyether ionophores and aromatic amidines. Antimicrobial Agents and Chemotherapy 35, 15201523.
Blagburn, B. L., Drain, K. L., Land, T. M., Moore, P. H., Kinard, R. G., Lindsay, D. S., Kumar, A., Shi, J., Boykin, D. W. and Tidwell, R. R. (1998 a). Dicationic furans inhibit the development of Cryptosporidium parvum in HSD/ICR suckling Swiss mice. Journal of Parasitology 84, 851856.
Blagburn, B. L., Drain, K. L., Land, T. M., Kinard, R. G., Hutton Moore, P., Lindsay, D. S., Patrick, D. A., Boykin, D. W. and Tidwell, R. R. (1998 b). Comparative efficacy evaluation of dicationic carbazole compounds, nitazoxanide and paromomycin against Cryptosporidium parvum infections in a neonatal mouse model. Antimicrobial Agents and Chemotherapy 42, 28772882.
Boere, R. T., Oakley, R. T. and Reed, R. W. (1987). Preparation of N,N,N′ tris(trimethylsilyl)amidines; a convenient route to unsubstituted amidines. Journal of Organometallic Chemistry 331, 161167.
Boykin, D. W., Kumar, A., Spychala, J., Zhou, M., Lombardy, R. J., Wilson, W. D., Dykstra, C. C., Jones, S. K., Hall, J. E., Tidwell, R. R., Laughton, C., Nunn, C. M. and Neidle, S. (1995). Dicationic diaryl furans as anti-Pneumocystis carinii agents. Journal of Medicinal Chemistry 38, 912916.
Boykin, D. W., Kumar, A., Hall, J. E., Bender, B. C. and Tidwell, R. R. (1996). Anti-pneumocystis activity of bis-amidoximes and bis-O-alkylamidoximes prodrugs. Bioorganic and Medicinal Chemistry Letters 6, 30173020.
Branowska, D., Farahat, A. A., Kumar, A., Wenzler, T., Brun, R., Liu, Y., Wilson, W. D. and Boykin, D. W. (2010). Synthesis and antiprotozoal activity of 2,5-bis[amidinoaryl]thiazoles. Bioorganic and Medicinal Chemistry 18, 35513558.
Bray, P. G., Barret, M. P., Ward, S. A. and De Koning, H. P. (2003). Pentamidine uptake and resistance in pathogenic protozoa: past, present and future. Trends in Parasitology 19, 232239.
Bustamante, J. M., Bixby, L. M. and Tarleton, R. L. (2008). Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. Nature Medicine 14, 542550.
Carlton, J. (2003). The Plasmodium vivax genome sequencing project. Trends in Parasitology 19, 227231.
Chackal-Catoen, S., Mao, Y., Wilson, W. D., Wenzler, T., Brun, R. and Boykin, D. W. (2006). Dicationic DNA-targeted antiprotozoal agents: naphthalene replacement of benzimidazole. Bioorganic and Medicinal Chemistry 14, 74347445.
Chowdhury, A. R., Bakshi, R., Wang, J., Yildirir, G., Liu, B., Pappas-Brown, V., Tolun, G., Griffith, J. D., Shapiro, T. A., Jensen, R. E. and Englund, P. T. (2010). The killing of African trypanosomes by ethidium bromide. PLoS Pathogens 6, 114.
Clement, B. and Raether, W. (1985). Amidoximes of pentamidine: synthesis, trypanocidal and leishmanicidal activity. Arzneimittelforschung 35, 10091014.
Collar, C., Zhu, X., Werbovetz, K., Boykin, D. and Wilson, W. (2011). Governing inhibition of arylimidamides against Leishmania: conservative computational modeling to improve chemotherapies. Bioorganic and Medicinal Chemistry 19, 45524561.
Cortes, H. C., Müller, N., Boykin, D., Stephens, C. E. and Hemphill, A. (2011). In vitro effects of arylimidamides against Besnoitia besnoiti infection in Vero cells. Parasitology 138, 583592.
Cory, M., Tidwell, R. R. and Fairly, T. A. (1992). Structure and DNA binding activity of analogues of 1,5-bis(4-amidinophenoxy)pentamidine (Pentamidine). Journal of Medicinal Chemistry 35, 431438.
Coura, J. R. and Borges-Pereira, J. (2012). Chagas disease. What is known and what should be improved: a systemic review. Revista Sociedade Brasileira de Medicina Tropical 45, 286296.
Croft, S. and Brazil, R. (1982). Effect of pentamidine isethionate on the ultrastructure and morphology of Leishmania mexicana amazonensis in vitro. Annals of Tropical Medicine and Parasitology 76, 3743.
Croft, S. and Olliaro, P. (2011). Leishmaniasis chemotherapy – challenges and opportunities. Clinical Microbiology and Infection 17, 14781483.
Daliry, A., Pires, M. Q., Silva, C. F., Pacheco, R. S., Munde, M., Stephens, C. E., Kumar, A., Ismail, M. A., Liu, Z., Farahat, A. A., Akay, S., Som, P., Hu, Q., Boykin, D. W., Wilson, W. D., De Castro, S. L. and Soeiro, M. N. C. (2011). The trypanocidal activity of amidine compounds does not correlate with their binding affinity to Trypanosoma cruzi kinetoplast DNA. Antimicrobial Agents and Chemotherapy 55, 47654773.
Das, B. P. and Boykin, D. W. (1977). Synthesis and antiprotozoal activity of 2,5-Bis-(4-guanylphenyl)furans. Journal of Medicinal Chemistry 20, 531536.
Das, V., Siddiqui, N., Pandey, K., Singh, V., Topno, R., Singh, D., Verma, R., Ranjan, A., Sinha, P. and Das, P. (2009). A controlled, randomized nonblinded clinical trial to assess the efficacy of amphotericin B deoxycholate as compared to pentamidine for the treatment of antimony unresponsive visceral leishmaniasis cases in Bihar, India. Therapeutics and Clinical Risk Management 5, 117124.
Da Silva, C. F., Batista, M. M., Batista, D. G., de Souza, E. M., da Silva, P. B., de Oliveira, G. M., Meuser, A. S., Shareef, A. R., Boykin, D. W. and Soeiro, M. N. C. (2008). In vitro and in vivo studies of the trypanocidal activity of a diarylthiophene diamidine against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 52, 33073314.
Da Silva, C. F., Junqueira, A., Lima, M. M., Romanha, A. J., Sales Junior, P. A., Stephens, C. E., Som, P., Boykin, D. W. and Soeiro, M. N. C. (2011 a). In vitro trypanocidal activity of DB745B and other novel arylimidamides against Trypanosoma cruzi. Journal of Antimicrobial Chemotherapy 66, 12951297.
Da Silva, C. F., Daliry, A., Silva, P. B., Akay, S., Banerjee, M., Farahat, A. A., Mary, K., Fisher, M. K., Hu, L., Kumar, A., Liu, Z., Stephens, C. E., Boykin, D. W. and Soeiro, M. N. C. (2011 b). The efficacy of arylimidamides against Trypanosoma cruzi in vitro. Parasitology 138, 18631869.
Da Silva, C. F., Batista, D. G., Oliveira, G. M., De Souza, E. M., Hammer, E. R., Silva, P. B., Anissa Daliry, A., Siciliano, J. A., Britto, C., Rodrigues, A. C. M., Liu, Z., Farahat, A. A., Kumar, A., Boykin, D. W. and Soeiro, M. N. C. (2012). In vitro and in vivo investigation of the efficacy of arylimidamide DB1831 and its mesylated salt form DB1965 – against Trypanosoma cruzi infection. PLoS One 7, e30356.
De Castro, S. L., Batista, D. G., Batista, M. M., Batista, W., Daliry, A., de Souza, E. M., Menna-Barreto, R. F., Oliveira, G. M., Salomão, K., Silva, C. F., Silva, P. B. and Soeiro, M. N. C. (2011). Experimental chemotherapy for Chagas disease: a morphological, biochemical, and proteomic overview of potential Trypanosoma cruzi targets of amidines derivatives and naphthoquinones. Molecular Biology International. Special Issue Target Identification and Intervention Strategies against Kinetoplastid Protozoan Parasites. doi 10.4061/2011/306928.
De Souza, E. M., Lansiaux, A., Bailly, C., Wilson, W. D., Hu, Q., Boykin, D. W., Batista, M. M., Araújo-Jorge, T. C. and Soeiro, M. N. C. (2004). Phenyl substitution of furamidine markedly potentiates its anti-parasitic activity against Trypanosoma cruzi and Leishmania amazonensis. Biochemical Pharmacology 15, 593600.
De Souza, E. M., Menna-Barreto, R., Araújo-Jorge, T. C., Kumar, A., Hu, Q., Boykin, D. W. and Soeiro, M. N. C. (2006). Antiparasitic activity of aromatic diamidines is related to apoptosis-like death in Trypanosoma cruzi. Parasitology 133, 7579.
De Souza, E. M., Oliveira, G. M. and Soeiro, M. C. N. (2007). Electrocardiographic findings in acutely and chronically T. cruzi-infected mice treated by a phenyl-substituted analogue of furamidine DB569. Drug Target Insights 2, 6169.
de Waal, D. T. and Combrink, M. P. (2006). Live vaccines against bovine babesiosis. Veterinary Parasitology 138, 8896.
Debache, K., Guionaud, C., Kropf, C., Boykin, D. W., Stephens, C. E. and Hemphill, A. (2011). Experimental treatment of Neospora caninum-infected mice with the arylimidamide DB750 and the thiazolide nitazoxanide. Experimental Parasitology 129, 95100.
Delves, M., Plouffe, D., Scheurer, C., Meister, S., Wittlin, S., Winzeler, E. A., Sinden, R. E. and Leroy, D. (2012). The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites. PLoS Medicine 9, e1001169.
Dias, J. C. (2009). Elimination of Chagas disease transmission: perspectives. Memorias do Instituto Oswaldo Cruz 104, 4145.
Donnelly, H., Bernard, E. M., Rothkotter, H., Gold, J. W. and Armstrong, D. (1988). Distribution of pentamidine in patients with AIDS. Journal of Infectious Diseases 157, 985989.
Dubey, J. P. (2009). History of the discovery of the life cycle of Toxoplasma gondii. International Journal for Parasitology 39, 877882.
Eloy, F. and Lenaers, R. (1962). The chemistry of amidoximes and related compounds. Chemical Reviews 62, 155183.
Farahat, A. A., Kumar, A., Say, M., Barghash, A. E. M., Goda, F. E., Eisa, H. M., Wenzler, T., Brun, R., Liu, Y., Mickelson, L., Wilson, W. D. and Boykin, D. W. (2010). Synthesis, DNA binding, fluorescence measurements and anti-parasitic activity of DAPI related diamidines. Bioorganic and Medicinal Chemistry 18, 557566.
Farahat, A. A., Paliakov, E., Kumar, A., Barghash, A. E. M., Goda, F. E., Eisa, H. M., Wenzler, T., Brun, R., Yang Liu, Y., Wilson, W. D. and Boykin, D. W. (2011). Exploration of larger central ring linkers in furamidine analogues: synthesis and evaluation of their DNA binding, antiparasitic and fluorescence properties. Bioorganic and Medicinal Chemistry 19, 21562167.
Feldman, D. M., Timms, D. and Borgida, D. F. (2010). Toxoplasmosis, parvovirus, and cytomegalovirus in pregnancy. Clinical Laboratory Medicine 30, 709720.
Gebre-Hiwot, A., Tadesse, G., Croft, S. and Frommel, D. (1992). An in vitro model for screening antileishmanial drugs: the human leukaemia monocyte cell line, THP-1. Acta Tropica 51, 237245.
Generaux, C. N., Ainslie, G. R., Bridges, A. S., Ismail, M. A., Boykin, D. W., Tidwell, R. R., Thakker, D. R. and Paine, M. F. (2013). Compartmental and enzyme kinetic modeling to elucidate the biotransformation pathway of a centrally acting antitrypanosomal prodrug. Drug Metabolism and Disposition 41, 518528.
Goa, K. L. and Campoli-Richards, D. M. (1987). Pentamidine isethionate. A review of its antiprotozoal activity, pharmacokinetics properties and therapeutic use in Pneumocystis carinii pneumonia. Drugs 33, 242258.
Goodsell, D. and Dickerson, R. E. (1986). Isohelical analysis of DNA groove-binding drugs. Journal of Medicinal Chemistry 29, 727733.
Hanson, W., Chapman, W. and Kinnamon, K. (1977). Testing of drugs for antileishmanial activity in golden hamsters infected with Leishmania donovani. International Journal for Parasitology 7, 443447.
Härdi, C., Haessig, M., Sager, H., Greif, G., Staubli, D. and Gottstein, B. (2006). Humoral immune reaction of newborn calves congenitally infected with Neospora caninum and experimentally treated with toltrazuril. Parasitology Research 99, 534540.
Hemphill, A., Esposito, M. and Müller, J. (2006). Nitazoxanide, a broad-spectrum thiazolide anti-infective agent for the treatment of gastrointestinal infections. Expert Opinion in Pharmacotherapy 7, 953964.
Henriquez, F. L., Woods, S., Cong, H., McLeod, R. and Roberts, C. W. (2010). Immunogenetics of Toxoplasma gondii informs vaccine design. Trends in Parasitology 26, 550555.
Hu, L. and Boykin, D. W. (2009). A novel and convenient synthesis of ‘reversed’ diamidino 2,5-aryl and 2,5-azaheterocycle-substituted furans. Synthesis 13, 21432145.
Hu, L., Arafa, R. K., Ismail, M. A., Wenzler, T., Brun, R., Munde, M., Wilson, W. D., Nzimiro, S., Samyesudhas, S., Werbovetz, K. A. and Boykin, D. W. (2008). Azaterphenyl diamidines as antileishmanial agents. Bioorganic and Medicinal Chemistry Letters 18, 247251.
Hu, L., Arafa, R. K., Ismail, M. A., Patel, A., Munde, M., Wilson, W. D., Wenzler, T., Brun, R. and Boykin, D. W. (2009). Synthesis and activity of azaterphenyl diamidines against Trypanosoma brucei rhodesience and Plasmodium falciparum. Bioorganic and Medicinal Chemistry 17, 66516658.
Hu, R., Kent, A., Adams, E., van der Veer, C., Sabajo, L., Mans, D., de Vries, H., Schallig, H. and Fat, R. (2012). Case report: first case of cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis in Suriname. American Journal of Tropical Medicine and Hygiene 86, 825827.
Huang, T., Vanden Eynde, J., Mayence, A., Donkor, I., Khan, S. and Tekwani, B. (2006). Anti-plasmodial and anti-leishmanial activity of conformationally restricted pentamidine congeners. Journal of Pharmacy and Pharmacology 58, 10331042.
Ismail, M. A., Brun, R., Easterbrook, J. D., Tanious, F. A., Wilson, W. D. and Boykin, D. W. (2003). Synthesis and antiprotozoal activity of aza-analogues of furamidine. Journal of Medicinal Chemistry 46, 47614769.
Ismail, M. A., Brun, R., Wenzler, T., Tanious, F. A., Wilson, W. D. and Boykin, D. W. (2004). Novel dicationic imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines as antiprotozoal agents. Journal of Medicinal Chemistry 47, 36583664.
Ismail, M. A., Batista-Parra, A., Miao, Y., Wilson, W. D., Wenzler, T., Brun, R. and Boykin, D. W. (2005). Dicationic near-linear biphenylbenzimidazole derivatives as DNA-targeted antiprotozoal agents. Bioorganic and Medicinal Chemistry 13, 67186726.
Ismail, M. A., Arafa, R. K., Reto, B. R., Wenzler, T., Miao, Y., Wilson, W. D., Generaux, C., Bridges, A., Hall, J. E. and Boykin, D. W. (2006). Synthesis, DNA affinity and antiprotozoal activity of linear dications: terphenyl diamidines and analogues. Journal of Medicinal Chemistry 49, 53245332.
Ismail, M. A., Arafa, R. K., Wenzler, T., Brun, R., Tanious, F. A., Wilson, W. D. and Boykin, D. W. (2008). Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines. Bioorganic and Medicinal Chemistry 16, 683691.
Ismail, M. A., El Bialy, S. A., Brun, R., Wenzler, T., Nanjunda, R., Wilson, W. D. and Boykin, D. W. (2011). Dicationic phenyl-2, 2′-bichalcophenes and analogues as antiprotozoal agents. Bioorganic and Medicinal Chemistry 19, 978984.
Jacquiet, P., Liénard, E. and Franc, M. (2010). Bovine besnoitiosis: epidemiological and clinical aspects. Veterinary Parasitology 174, 3036.
Judkins, B. D., Allen, D. G., Cook, T. A., Evans, B. and Sardharwala, T. E. (1996). A versatile synthesis of amidines from nitriles via amidoximes. Synthetic Communications 26, 43514367.
King, H., Lourie, E. M. and Yorke, W. (1937). New trypanocidal substances. Lancet II, 13601363.
Kjemtrup, A. M. and Conrad, P. A. (2000). Human babesiosis: an emerging tick-borne disease. International Journal for Parasitology 30, 13231337.
Klingbeil, M. M., Drew, M. E., Liu, Y., Morris, J. C., Motyka, S. A., Saxowsky, T. T., Wang, Z. and Englund, P. T. (2001). Unlocking the secrets of trypanosome kinetoplast DNA network replication. Protist 152, 255262.
Kotthaus, J., Schade, D., Schwering, U., Hungeling, H., Muller-Fielitz, H., Raasch, W. and Clement, B. (2011). New prodrugs of the antiprotozoal drug pentamidine. Chem Med Chem 6, 22332242.
Kropf, C., Debache, K., Rampa, C., Barna, F., Schorer, M., Stephens, C. E., Ismail, M. A., Boykin, D. W. and Hemphill, A. (2012). The adaptive potential of a survival artist: characterization of the in vitro interactions of Toxoplasma gondii tachyzoites with di-cationic compounds in human fibroblast cell cultures. Parasitology 139, 208220.
Lai, D. H., Hashimi, H., Lun, Z. R., Ayala, F. J. and Lukes, J. (2008). Adaptations of Trypanosoma brucei to gradual loss of kinetoplast DNA: Trypanosoma equiperdum and Trypanosoma evansi are petite mutants of T. brucei. Proceedings of the National Academy of Sciences USA 105, 19992004.
Lallemand, M., Villeneuve, A., Belda, J. and Dubreuil, P. (2006). Field study of the efficacy of halofuginone and decoquinate in the treatment of cryptosporidiosis in veal calves. Veterinary Record 159, 672676.
Lanteri, C. A., Stewart, M. L., Brock, J. M., Alibu, V. P., Meshnick, S. R., Tidwell, R. R. and Barrett, M. P. (2006). Roles for the Trypanosoma brucei P2 transporter in DB75 uptake and resistance. Molecular Pharmacology 70, 15851592.
Leepin, A., Stüdli, A., Brun, R., Stephens, C. E., Boykin, D. W. and Hemphill, A. (2008). Host cells participate in the in vitro effects of novel diamidine analogues against tachyzoites of the intracellular apicomplexan parasites Neospora caninum and Toxoplasma gondii. Antimicrobial Agents and Chemotherapy 52, 19992008.
Lefay, D., Naciri, M., Poirier, P. and Chermette, R. (2001). Efficacy of halofuginone lactate in the prevention of cryptosporidiosis in suckling calves. Veterinary Record 148, 108112.
Lepesheva, G. I. and Waterman, M. R. (2011). Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis. Current Topics in Medicinal Chemistry 11, 20602071.
Lindsay, D. S., Blagburn, B. L., Hall, J. E. and Tidwell, R. R. (1991). Activity of pentamidine and pentamidine analogs against Toxoplasma gondii in cell cultures. Antimicrobial Agents and Chemotherapy 35, 19141916.
Lown, J. W. (1994). DNA recognition by lexitropsins, minor groove binding agents. Journal of Molecular Recognition 7, 7988.
Macharia, J., Bourdichon, A. and Gicheru, M. (2004). Efficacy of trypan: a diminazene based drug as antileishmanial agent. Acta Tropica 92, 267272.
Marin-Neto, J. A. and Rassi, A. Jr. (2009). Update on Chagas heart disease on the first centenary of its discovery. Revista Espanhola de Cardiologia 62, 12111216.
Mäser, P, Wittlin, S., Rottmann, M., Wenzler, T., Kaiser, M. and Brun, R. (2012). Antiparasitic agents: new drugs on the horizon. Current Opinion in Pharmacology 12, 562566.
Mathis, A. M., Holman, J. L., Sturk, L. M., Ismail, M. A., Boykin, D. W., Tidwell, R. R. and Hall, J. E. (2006). Accumulation and intracellular distribution of antitrypanosomal diamidine compounds DB75 and DB820 in African trypanosomes. Antimicrobial Agents and Chemotherapy 50, 21852191.
Mathis, A. M., Bridges, A. S., Ismail, M. A., Kumar, A., Francesconi, I., Anbazhagan, M., Hu, Q., Tanious, F. A., Wenzler, T., Saulter, J., Wilson, W. D., Brun, R., Boykin, D. W., Tidwell, R. R. and Hall, J. E. (2007). Diphenyl furans and aza analogs: effects of structural modification on in vitro activity, DNA binding, and accumulation and distribution in trypanosomes. Antimicrobial Agents and Chemotherapy 51, 28012810.
Mayence, A., Vanden Eynde, J., LeCour, L. J., Walker, L., Tekwani, B. and Huang, T. (2004). Piperazine-linked bisbenzamidines: a novel class of antileishmanial agents. European Journal of Medicinal Chemistry 39, 547553.
McKerrow, J. H., Doyle, P. S., Engel, J. C., Podust, L. M., Robertson, S. A., Ferreira, R., Saxton, T., Arkin, M., Kerr, I. D., Brinen, L. S. and Craik, C. S. (2009). Two approaches to discovering and developing new drugs for Chagas disease. Memorias do Instituto Oswaldo Cruz 104, 263269.
Mdachi, R. E., Thuita, J. K., Kagira, J. M., Ngotho, J. M., Murilla, G. A., Ndung'u, J. M., Tidwell, R. R., Hall, J. E. and Brun, R. (2009). Efficacy of the novel diamidine compound 2,5-Bis(4-amidinophenyl)- furan-bis-O-methlylamidoxime (Pafuramidine, DB289) against Trypanosoma brucei rhodesiense infection in vervet monkeys after oral administration. Antimicrobial Agents and Chemotherapy 53, 953957.
Miao, Y., Lee, M., Batista-Parra, A., Ismail, M. A., Neidle, S., Boykin, D. W. and Wilson, W. D. (2005). Out of shape DNA minor groove binders induced fit interactions of heterocyclic dications with the DNA minor groove. Biochemistry 44, 1470114708.
Midgley, I., Fitzpatrick, K., Taylor, L. M., Houchen, T. L., Henderson, S. J., Wright, S. J., Cybulski, Z. R., John, B. A., McBurney, A., Boykin, D. W. and Trendler, K. L. (2007). Pharmacokinetics and metabolism of the prodrug DB289 (2,5-bis[4-(N-methoxyamidino)phenyl]furan monomaleate) in rat and monkey and its conversion to the antiprotozoal/antifungal drug DB75 (2,5-bis(4-guanylphenyl)furan dihydrochloride). Drug Metabolism and Disposition 35, 955967.
Molina, J., Martins-Filho, O., Brener, Z., Romanha, A. J., Loebenberg, D. and Urbina, J. A. (2000). Activities of the triazole derivative SCH 56592 (posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts. Antimicrobial Agents and Chemotherapy 44, 150155.
Monney, T., Debache, K. and Hemphill, A. (2011). Vaccines against a major cause of abortion in cattle, Neospora caninum infection. Animals 1, 306325.
Müller, J. and Hemphill, A. (2013). In vitro culture systems for the study of apicomplexan parasites in farm animals. International Journal for Parasitology 43, 115124.
Nehrbass-Stüdli, A., Boykin, D., Tidwell, R. R. and Brun, R. (2011). Novel diamidines with activity against Babesia divergens in vitro and Babesia microti in vivo. Antimicrobial Agents and Chemotherapy 55, 34393445.
Neves, L., Talhari, A., Gadelha, E., Silva Júnior, R., Guerra, J., Ferreira, L. and Talhari, S. (2011). A randomized clinical trial comparing meglumine antimoniate, pentamidine and amphotericin B for the treatment of cutaneous leishmaniasis by Leishmania guyanensis. Anais Brasileiros de Dermatologia 86, 10921101.
Nguygen, B., Lee, M. P., Hamelberg, D., Joubert, A., Bailly, C., Brun, R., Neidle, S. and Wilson, W. D. (2002). Strong binding in the DNA minor groove by an aromatic diamidine with a shape that does not match the curvature of the groove. Journal of the American Chemical Society 124, 1368013681.
Nguygen, B., Hamelberg, D., Bailly, C., Colson, P., Stanek, J., Brun, R., Neidle, S. and Wilson, W. D. (2004). Characterization of a novel DNA minor-groove complex. Biophysical Journal 86, 10281041.
Nguyen, B., Boykin, D. W. and Wilson, W. D. (2007). DNA minor groove interactions of antiparasitic diamidines: re-evaluation of the crescent-shape concept in groove-binding. In Synthetic and Biophysical Studies of DNA Binding Compounds (ed. Lee, M. and Strekowski, L.) Chap 2. Transworld Research Network, Trivandrum–695023, Kerala, India.
Olliaro, P., Guerin, P., Gerstl, S., Haaskjold, A., Rottingen, J. and Sundar, S. (2005). Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980–2004. Lancet Infectious Diseases 5, 763774.
Pacheco, M. G., da Silva, C. F., de Souza, E. M., Batista, M. M., da Silva, P. B., Kumar, A., Stephens, C. E., Boykin, D. W. and Soeiro, M. N. C. (2009). Trypanosoma cruzi: activity of heterocyclic cationic molecules in vitro. Experimental Parasitology 123, 7380.
Paine, M. F., Wang, M. Z., Generaux, C. N., Boykin, D. W., Wilson, W. D., De Koning, H. P., Olson, C. A., Pohlig, G., Burri, C., Brun, R., Murilla, G. A., Thuita, J. K., Barrett, M. P. and Tidwell, R. R. (2010). Diamidines for human African trypanosomiasis. Current Opinions in Investigational Drugs 11, 876883.
Picado, A., Rijal, S., Sundar, S. and Boelaert, M. (2012). Visceral leishmaniasis treatment in the Indian subcontinent: how to reach the most vulnerable. Expert Review of Anti-Infective Therapy 10, 839841.
Pinner, A. and Klein, F. (1877). Umwandlung der nitrile in imide. Berichte der deutschen chemischen Gesellschaft 10, 18891897.
Purfield, A. E., Tidwell, R. R. and Meshnick, S. R. (2009). The diamidine DB75 targets the nucleus of Plasmodium falciparum. Malaria Journal 8, 104.
Reid, C., Farahat, A., Zhu, X., Pandharkar, T., Boykin, D. and Werbovetz, K. (2012). Antileishmanial bis-arylimidamides: DB766 analogs modified in the linker region and bis-arylimidamide structure-activity relationships. Bioorganic and Medicinal Chemistry Letters 22, 68066810.
Rocha, M. O., Teixeira, M. M. and Ribeiro, A. L. (2007). An update on the management of Chagas cardiomyopathy. Expert Review Anti Infective Therapy 5, 727743.
Roger, R. and Neilson, D. G. (1961). The chemistry of imidates. Chemical Reviews 61, 179211.
Romanha, A. J., Castro, S. L., Soeiro, M. N. C., Lannes-Vieira, J., Ribeiro, I., Talvani, A., Bourdin, B., Blum, B., Olivieri, B., Zani, C., Spadafora, C., Chiari, E., Chatelain, E., Chaves, G., Calzada, J. E., Bustamante, J. M., Freitas-Junior, L. H., Romero, L. I., Bahia, M. T., Lotrowska, M., Soares, M., Andrade, S. G., Armstrong, T., Degrave, W. and Andrade, Z. A. (2010). In vitro and in vivo experimental models for drug screening and development for Chagas disease. Memórias do Instuto Oswaldo Cruz 105, 233238.
Sands, M., Kron, M. A. and Brown, R. A. (1985). Pentamidine: a review. Reviews in Infectious Diseases 7, 625634.
Saulter, J. Y. (2005). Permeability and Metabolism of Potential Prodrugs for the Antimicrobial Agent 2,5 bis(4-amidinophenyl)furan (DB75) [3170543]. The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Saulter, J. Y., Kurian, J. R., Trepanier, L. A., Tidwell, R. R., Bridges, A. S., Boykin, D. W., Stephens, C. E., Anbazhagan, M. and Hall, J. E. (2005). Unusual dehydroxylation of antimicrobial amidoxime prodrugs by cytochrome b5 and NADH cytochrome b5 reductase. Drug Metabolism and Disposition 33, 18861893.
Schnaufer, A., Panigrahi, A. K., Panicucci, B., Igo, R. P. Jr., Wirtz, E., Salavati, R. and Stuart, K. (2001). An RNA ligase essential for RNA editing and survival of the bloodstream form of Trypanosoma brucei. Science 291, 21592162.
Schnaufer, A., Domingo, G. J. and Stuart, K. (2002). Natural and induced dyskinetoplastic trypanosomatids: how to live without mitochondrial DNA. International Journal for Parasitology 32, 10711084.
Schnaufer, A., Clark-Walker, G. D., Steinberg, A. G. and Stuart, K. (2005). The F1-ATP synthase complex in bloodstream stage trypanosomes has an unusual and essential function. EMBO Journal 24, 40294040.
Schnyder, M., Kohler, L., Hemphill, A. and Deplazes, P. (2009). Prophylactic and therapeutic efficacy of nitazoxanide against Cryptosporidium parvum in experimentally challenged neonatal calves. Veterinary Parasitology 160, 149154.
Schorer, M., Debache, K., Barna, F., Monney, T., Boykin, D. W., Stephens, C. E. and Hemphill, A. (2012). Di-cationic arylimidamides act against Neospora caninum tachyzoites by interference in membrane structure and nucleolar integrity and are active against challenge infection in mice. International Journal for Parasitology: Drugs and Drug Resistance 2, 109120.
Shapiro, T. A. and Englund, P. T. (1990). Selective cleavage of kinetoplast DNA minicircles promoted by antitrypanosomal drugs. Proceedings of the National Academy of Sciences USA 87, 950954.
Shapiro, T. A. and Englund, P. T. (1995). The structure and replication of kinetoplast DNA. Annual Review of Microbiology 49, 117143.
Shriner, R. l. and Neumann, F. W. (1944). The chemistry of the amidines. Chemical Reviews 35, 351425.
Silva, C. F., Batista, M. M., Mota, R. A., de Souza, E. M., Stephens, C. E., Som, P., Boykin, D. W. and Soeiro, M. N. C. (2007). Activity of ‘reversed’ diamidines against Trypanosoma cruziin vitro’. Biochemical Pharmacology 15, 19391946.
Singh, N., Kumar, M. and Singh, R. K. (2012). Leishmanaiasis: current status of available drugs and new potential drug targets. Asian Pacific Journal of Tropical Medicine 485497.
Soeiro, M. N. and de Castro, S. L. (2009). Trypanosoma cruzi targets for new chemotherapeutic approaches. Expert Opinion on Therapeutic Targets 13, 105121.
Soeiro, M. N., De Souza, E. M., Stephens, C. E. and Boykin, D. W. (2005). Aromatic diamidines as antiparasitic agents. Expert Opinion on Investigational Drugs 14, 957972.
Soeiro, M. N., de Castro, S. L., de Souza, E. M., Batista, D. G., Silva, C. F. and Boykin, D. W. (2008). Diamidine activity against trypanosomes: the state of the art. Current Molecular Pharmacology 1, 151161.
Soeiro, M. N. C. and de Castro, S. L. (2011). Screening of potential anti-Trypanosoma cruzi candidates: in vitro and in vivo studies. Open Medicinal Chemistry Journal 5, 2130.
Stadelmann, B., Kuster, T., Scholl, S., Barna, F., Kropf, C., Keiser, J., Boykin, D. W., Stephens, C. E. and Hemphill, A. (2011). In vitro efficacy of di-cationic compounds (pentamidine analogs) and mefloquine-enantiomers against Echinococcus multilocularis metacestodes. Antimicrobial Agents and Chemotherapy 55, 48664872.
Stead, A. M., Bray, P. G., Edwards, I. G., De Koning, H. P., Elford, B. C., Stocks, P. A. and Ward, S. A. (2001). Diamidine compounds: selective uptake and targeting in Plasmodium falciparum. Molecular Pharmacology 59, 12981306.
Steck, E., Kinnamon, K., Rane, D. and Hanson, W. (1981). Leishmania donovani, Plasmodium berghei, Trypanosoma rhodesiense: antiprotozoal effects of some amidine types. Experimental Parasitology 52, 1981.
Stephens, C. E., Tanious, F., Kim, S., Wilson, W. D., Schell, W. A., Perfect, J. R., Franzblau, S. G. and Boykin, D. W. (2001). Diguanidino and ‘Reversed’ diamidino 2,5-Diarylfurans as antimicrobial agents. Journal of Medicinal Chemistry 44, 17411748.
Stephens, C., Brun, R., Salem, M., Werbovetz, K., Tanious, F., Wilson, W. and Boykin, D. (2003). The activity of diguanidino and ‘reversed’ diamidino 2,5-diarylfurans versus Trypanosoma cruzi and Leishmania donovani. Bioorganic Medicinal and Chemistry Letters 13, 20652069.
Stewart, M. L., Krishna, S., Burchmore, R. J., Brun, R., de Koning, H. P., Boykin, D. W., Tidwell, R. R., Hall, J. E. and Barrett, M. P. (2005). Detection of arsenical drug resistance in Trypanosoma brucei with a simple fluorescence test. Lancet 366, 486487.
Thuita, J. K., Wang, M. Z., Kagira, J. M., Denton, C. L., Paine, M. F., Mdachi, R. E., Murilla, G. A., Ching, S., Boykin, D. W., Tidwell, R. R., Hall, J. E. and Brun, R. (2012). Pharmacology of DB844, an orally active aza analogue of pafuramidine, in a monkey model of second stage human African trypanosomiasis. PLoS Neglected Tropical Diseases 6, e1734.
Tidwell, R. R. and Boykin, D. W. (2003) Dicationic DNA minor groove binders as antimicrobial agents. In Small Molecule DNA and RNA Binders: From Synthesis to Nucleic Acid Complexes (ed. Demeunynck, M., Bailly, C. and Wilson, W. D.), Vol. 2, pp. 414460. Wiley-VCH, New York, USA.
Urbina, J. A., Payares, G., Contreras, L. M., Liendo, A., Sanoja, C., Molina, J., Piras, M., Piras, R., Perez, N., Wincker, P. and Loebenberg, D. (1998). Antiproliferative effects and mechanism of action of SCH 56592 against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies. Antimicrobial Agents and Chemotherapy 42, 17711777.
Urbina, J. A., Payares, G., Sanoja, C., Lira, R. and Romanha, A. J. (2003). In vitro and in vivo activities of ravuconazole on Trypanosoma cruzi, the causative agent of Chagas disease. International Journal of Antimicrobial Agents 21, 2738.
van der Meide, W., Sabajo, L., Jensema, A., Peekel, I., Faber, W., Schallig, H. and Fat, R. (2009). Evaluation of treatment with pentamidine for cutaneous leishmaniasis in Suriname. International Journal of Dermatology 48, 5258.
Vial, H. J. and Gorenflot, A. (2006). Chemotherapy against babesiosis. Veterinary Parasitology 138, 147160.
Wang, M. Z., Saulter, J. Y., Usuki, E., Cheung, Y. L., Hall, M., Bridges, A. S., Loewen, G., Parkinson, O. T., Stephens, C. E., Allen, J. L., Zeldin, D. C., Boykin, D. W., Tidwell, R. R., Parkinson, A., Paine, M. F. and Hall, J. E. (2006). CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime]. Drug Metabolism and Disposition 34, 19851994.
Wang, M. Z., Wu, J. Q., Bridges, A. S., Zeldin, D. C., Kornbluth, S., Tidwell, R. R., Hall, J. E. and Paine, M. F. (2007). Human enteric microsomal CYP4F enzymes O-demethylate the anti-parasitic prodrug pafuramidine. Drug Metabolism Dispose 35, 20672075.
Wang, M. Z., Zhu, X., Srivastava, A., Liu, Q., Sweat, J. M., Pandharkar, T., Stephens, C. E., Riccio, E., Parman, T., Munde, M., Mandal, S., Madhubala, R., Tidwell, R. R., Wilson, W. D., Boykin, D. W., Hall, J. E., Kyle, D. E. and Werbovetz, K. A. (2010). Novel arylimidamides for the treatment of visceral leishmaniasis. Antimicrobial Agents and Chemotherapy 54, 25072516.
Wang, Z. and Englund, P. T. (2001). RNA interference of a trypanosome topoisomerase II causes progressive loss of mitochondrial DNA. European Molecular Biology Organization Journal 20, 46744683.
Ward, C. P., Burgess, K. E., Burchmore, R. J., Barrett, M. P. and de Koning, H. P. (2010). A fluorescence-based assay for the uptake of CPD0801 (DB829) by African trypanosomes. Molecular and Biochemical Parasitology 174, 145149.
Wenzler, T., Boykin, D. W., Ismail, M. A., Hall, J. E., Tidwell, R. R. and Brun, R. (2009). New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289. Antimicrobial Agents and Chemotherapy 53, 41854192.
Werbovetz, K. A. (2006). Diamidines as antitrypanosomal, antileishmanial and antimalarial agents. Current Opinion in Investigational Drugs 7, 147157.
Wilson, W. D., Tanious, F. A., Buczak, H., Venkatramanan, M. K., Das, B. P. and Boykin, D. W. (1990). The effects of ligand structure on binding mode and specificity in the interaction of unfused aromatic cations with DNA. In The Jerusalem Symposia on Quantum Chemistry and Biochemistry (ed. Pulman, B. and Jortner, J.), 23331353. Kluwer Academic Publishers, Dordrecht, the Netherlands.
Wilson, W. D., Nguyen, B., Tanious, F. A., Mathis, A., Hall, J. E., Stephens, C. E. and Boykin, D. W. (2005). Dications that target the DNA minor groove: compound design and preparation, DNA interactions, cellular distribution and biological activity. Current Medicinal Chemistry – Anti-Cancer Agents 5, 389408.
Wilson, W. D., Tanious, F. A., Mathis, A., Tevis, D., Hall, J. E. and Boykin, D. W. (2008). Antiparasitic compounds that target DNA. Biochimie 90, 9991014.
World Health Organization (2010). Control of the Leishmaniasis. WHO Technical Report Series No. 949. World Health Organization, Geneva, Switzerland.
Zhou, L., Lee, K., Thaker, D. R., Boykin, D. W., Tidwell, R. R. and Hall, J. E. (2002). Enhanced permeability of the antimicrobial agent 2,5-bis(4-amidinophenyl)furan across Caco-2 cell monolayers via its methylamidoidme prodrug. Pharmaceutical Research 19, 16891695.
Zhu, X., Liu, Q., Yang, S., Parman, T., Green, C., Mirsalis, J., Soeiro, M. N., de Souza, E. M., da Batista, C. F., da Gama Jaen Batista, D., Stephens, C. E., Banerjee, M., Abdelbasset Farahat, A. A., Munde, M., Wilson, W. D., Boykin, D. W., Wang, M. Z. and Werbovetz, K. (2012). Evaluation of arylimidamides DB1955 and DB1960 as candidates against visceral Leishmaniasis and Chagas Disease – in vivo efficacy, acute toxicity, pharmacokinetics and toxicology studies. Antimicrobial Agents and Chemotherapy 56, 36903699.
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