Hostname: page-component-cd9895bd7-fscjk Total loading time: 0 Render date: 2024-12-23T04:24:58.536Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  08 April 2013

M. N. C. SOEIRO ,
K. WERBOVETZ ,
D. W. BOYKIN ,
W. D. WILSON ,
M. Z. WANG  and
A. HEMPHILL
M. N. C. SOEIRO*
Affiliation:
Laboratόrio de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
K. WERBOVETZ
Affiliation:
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
D. W. BOYKIN
Affiliation:
Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA
W. D. WILSON
Affiliation:
Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA
M. Z. WANG
Affiliation:
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA
A. HEMPHILL
Affiliation:
Institute of Parasitology, Vetsuisse Faculty of Veterinary Medicine, University of Berne, Berne, Switzerland
*
*Corresponding author: Laboratόrio de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

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.

Keywords

intracellular parasiteschemotherapyaromatic amidinesarylimidamides
Type
Review Article
Information
Parasitology , Volume 140 , Issue 8 , July 2013 , pp. 929 - 951
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

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.CrossRefGoogle ScholarPubMed
Aly, A. A. and Nour-El-Din, A. M. (2008). Functionality of amidines and amidrazones. Archive for Organic Chemistry 153–194.Google Scholar
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, 497–500.CrossRefGoogle ScholarPubMed
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, 211–226.CrossRefGoogle ScholarPubMed
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, 5480–5488.CrossRefGoogle ScholarPubMed
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, 103–116.CrossRefGoogle Scholar
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, 254–272.CrossRefGoogle Scholar
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, 5807–5823.CrossRefGoogle ScholarPubMed
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, 4657–4667.CrossRefGoogle ScholarPubMed
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, 449–454.CrossRefGoogle ScholarPubMed
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, 795–836.CrossRefGoogle Scholar
Barrett, M. P., Burchmore, R. J. S., Stich, A., Lazzari, J. O., Frasch, A. C. and Cazzulo, J. J. (2003). The trypanosomiases. Lancet 362, 1469–1480.CrossRefGoogle ScholarPubMed
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, 1155–1171.CrossRefGoogle ScholarPubMed
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, 3731–3738.CrossRefGoogle ScholarPubMed
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, 223–234.CrossRefGoogle ScholarPubMed
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, 2940–2952.CrossRefGoogle ScholarPubMed
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, 251–259.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 1381–1386.CrossRefGoogle ScholarPubMed
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, 1825–1831.CrossRefGoogle ScholarPubMed
Berman, J. and Wyler, D. (1980). An in vitro model for investigation of chemotherapeutic agents in leishmaniasis. Journal of Infectious Diseases 142, 83–86.CrossRefGoogle Scholar
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, 1520–1523.CrossRefGoogle ScholarPubMed
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, 851–856.CrossRefGoogle ScholarPubMed
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, 2877–2882.CrossRefGoogle Scholar
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, 161–167.CrossRefGoogle Scholar
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, 912–916.CrossRefGoogle Scholar
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, 3017–3020.CrossRefGoogle Scholar
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, 3551–3558.CrossRefGoogle Scholar
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, 232–239.CrossRefGoogle ScholarPubMed
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, 542–550.CrossRefGoogle ScholarPubMed
Carlton, J. (2003). The Plasmodium vivax genome sequencing project. Trends in Parasitology 19, 227–231.CrossRefGoogle ScholarPubMed
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, 7434–7445.CrossRefGoogle ScholarPubMed
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, 1–14.Google Scholar
Clement, B. and Raether, W. (1985). Amidoximes of pentamidine: synthesis, trypanocidal and leishmanicidal activity. Arzneimittelforschung 35, 1009–1014.Google ScholarPubMed
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, 4552–4561.CrossRefGoogle ScholarPubMed
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, 583–592.CrossRefGoogle ScholarPubMed
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, 431–438.CrossRefGoogle Scholar
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, 286–296.CrossRefGoogle ScholarPubMed
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, 37–43.CrossRefGoogle ScholarPubMed
Croft, S. and Olliaro, P. (2011). Leishmaniasis chemotherapy – challenges and opportunities. Clinical Microbiology and Infection 17, 1478–1483.CrossRefGoogle ScholarPubMed
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, 4765–4773.CrossRefGoogle Scholar
Das, B. P. and Boykin, D. W. (1977). Synthesis and antiprotozoal activity of 2,5-Bis-(4-guanylphenyl)furans. Journal of Medicinal Chemistry 20, 531–536.CrossRefGoogle ScholarPubMed
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, 117–124.Google ScholarPubMed
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, 3307–3314.CrossRefGoogle ScholarPubMed
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, 1295–1297.CrossRefGoogle ScholarPubMed
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, 1863–1869.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 593–600.CrossRefGoogle Scholar
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, 75–79.CrossRefGoogle ScholarPubMed
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, 61–69.CrossRefGoogle ScholarPubMed
de Waal, D. T. and Combrink, M. P. (2006). Live vaccines against bovine babesiosis. Veterinary Parasitology 138, 88–96.CrossRefGoogle ScholarPubMed
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, 95–100.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Dias, J. C. (2009). Elimination of Chagas disease transmission: perspectives. Memorias do Instituto Oswaldo Cruz 104, 41–45.CrossRefGoogle ScholarPubMed
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, 985–989.CrossRefGoogle ScholarPubMed
Dubey, J. P. (2009). History of the discovery of the life cycle of Toxoplasma gondii. International Journal for Parasitology 39, 877–882.CrossRefGoogle ScholarPubMed
Eloy, F. and Lenaers, R. (1962). The chemistry of amidoximes and related compounds. Chemical Reviews 62, 155–183.CrossRefGoogle Scholar
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, 557–566.CrossRefGoogle Scholar
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, 2156–2167.CrossRefGoogle ScholarPubMed
Feldman, D. M., Timms, D. and Borgida, D. F. (2010). Toxoplasmosis, parvovirus, and cytomegalovirus in pregnancy. Clinical Laboratory Medicine 30, 709–720.CrossRefGoogle ScholarPubMed
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, 237–245.CrossRefGoogle Scholar
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, 518–528.CrossRefGoogle ScholarPubMed
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, 242–258.CrossRefGoogle ScholarPubMed
Goodsell, D. and Dickerson, R. E. (1986). Isohelical analysis of DNA groove-binding drugs. Journal of Medicinal Chemistry 29, 727–733.CrossRefGoogle ScholarPubMed
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, 443–447.CrossRefGoogle ScholarPubMed
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, 534–540.CrossRefGoogle Scholar
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, 953–964.CrossRefGoogle ScholarPubMed
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, 550–555.CrossRefGoogle ScholarPubMed
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, 2143–2145.Google Scholar
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, 247–251.CrossRefGoogle ScholarPubMed
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, 6651–6658.CrossRefGoogle Scholar
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, 825–827.CrossRefGoogle ScholarPubMed
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, 1033–1042.CrossRefGoogle ScholarPubMed
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, 4761–4769.CrossRefGoogle ScholarPubMed
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, 3658–3664.CrossRefGoogle Scholar
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, 6718–6726.CrossRefGoogle Scholar
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, 5324–5332.CrossRefGoogle ScholarPubMed
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, 683–691.CrossRefGoogle Scholar
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, 978–984.CrossRefGoogle Scholar
Jacquiet, P., Liénard, E. and Franc, M. (2010). Bovine besnoitiosis: epidemiological and clinical aspects. Veterinary Parasitology 174, 30–36.CrossRefGoogle ScholarPubMed
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, 4351–4367.CrossRefGoogle Scholar
King, H., Lourie, E. M. and Yorke, W. (1937). New trypanocidal substances. Lancet II, 1360–1363.CrossRefGoogle Scholar
Kjemtrup, A. M. and Conrad, P. A. (2000). Human babesiosis: an emerging tick-borne disease. International Journal for Parasitology 30, 1323–1337.CrossRefGoogle ScholarPubMed
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, 255–262.CrossRefGoogle ScholarPubMed
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, 2233–2242.CrossRefGoogle ScholarPubMed
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, 208–220.CrossRefGoogle ScholarPubMed
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, 1999–2004.CrossRefGoogle ScholarPubMed
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, 672–676.CrossRefGoogle ScholarPubMed
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, 1585–1592.CrossRefGoogle ScholarPubMed
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, 1999–2008.CrossRefGoogle ScholarPubMed
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, 108–112.CrossRefGoogle ScholarPubMed
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, 2060–2071.CrossRefGoogle ScholarPubMed
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, 1914–1916.CrossRefGoogle ScholarPubMed
Lown, J. W. (1994). DNA recognition by lexitropsins, minor groove binding agents. Journal of Molecular Recognition 7, 79–88.CrossRefGoogle ScholarPubMed
Macharia, J., Bourdichon, A. and Gicheru, M. (2004). Efficacy of trypan: a diminazene based drug as antileishmanial agent. Acta Tropica 92, 267–272.CrossRefGoogle ScholarPubMed
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, 1211–1216.CrossRefGoogle ScholarPubMed
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, 562–566.CrossRefGoogle ScholarPubMed
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, 2185–2191.CrossRefGoogle ScholarPubMed
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, 2801–2810.CrossRefGoogle ScholarPubMed
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, 547–553.CrossRefGoogle ScholarPubMed
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, 263–269.CrossRefGoogle ScholarPubMed
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, 953–957.CrossRefGoogle Scholar
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, 14701–14708.CrossRefGoogle ScholarPubMed
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, 955–967.CrossRefGoogle Scholar
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, 150–155.CrossRefGoogle ScholarPubMed
Monney, T., Debache, K. and Hemphill, A. (2011). Vaccines against a major cause of abortion in cattle, Neospora caninum infection. Animals 1, 306–325.CrossRefGoogle Scholar
Müller, J. and Hemphill, A. (2013). In vitro culture systems for the study of apicomplexan parasites in farm animals. International Journal for Parasitology 43, 115–124.CrossRefGoogle Scholar
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, 3439–3445.CrossRefGoogle Scholar
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, 1092–1101.CrossRefGoogle ScholarPubMed
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, 13680–13681.CrossRefGoogle Scholar
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, 1028–1041.CrossRefGoogle Scholar
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.Google Scholar
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, 763–774.CrossRefGoogle ScholarPubMed
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, 73–80.CrossRefGoogle ScholarPubMed
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, 876–883.Google ScholarPubMed
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, 839–841.CrossRefGoogle ScholarPubMed
Pinner, A. and Klein, F. (1877). Umwandlung der nitrile in imide. Berichte der deutschen chemischen Gesellschaft 10, 1889–1897.CrossRefGoogle Scholar
Purfield, A. E., Tidwell, R. R. and Meshnick, S. R. (2009). The diamidine DB75 targets the nucleus of Plasmodium falciparum. Malaria Journal 8, 104.CrossRefGoogle ScholarPubMed
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, 6806–6810.CrossRefGoogle ScholarPubMed
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, 727–743.CrossRefGoogle ScholarPubMed
Roger, R. and Neilson, D. G. (1961). The chemistry of imidates. Chemical Reviews 61, 179–211.CrossRefGoogle Scholar
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, 233–238.CrossRefGoogle ScholarPubMed
Sands, M., Kron, M. A. and Brown, R. A. (1985). Pentamidine: a review. Reviews in Infectious Diseases 7, 625–634.CrossRefGoogle ScholarPubMed
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.Google Scholar
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, 1886–1893.Google ScholarPubMed
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, 2159–2162.CrossRefGoogle ScholarPubMed
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, 1071–1084.CrossRefGoogle ScholarPubMed
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, 4029–4040.CrossRefGoogle ScholarPubMed
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, 149–154.CrossRefGoogle ScholarPubMed
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, 109–120.Google ScholarPubMed
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, 950–954.CrossRefGoogle ScholarPubMed
Shapiro, T. A. and Englund, P. T. (1995). The structure and replication of kinetoplast DNA. Annual Review of Microbiology 49, 117–143.CrossRefGoogle ScholarPubMed
Shriner, R. l. and Neumann, F. W. (1944). The chemistry of the amidines. Chemical Reviews 35, 351–425.CrossRefGoogle Scholar
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 cruzi ‘in vitro’. Biochemical Pharmacology 15, 1939–1946.CrossRefGoogle Scholar
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 485–497.Google Scholar
Soeiro, M. N. and de Castro, S. L. (2009). Trypanosoma cruzi targets for new chemotherapeutic approaches. Expert Opinion on Therapeutic Targets 13, 105–121.CrossRefGoogle ScholarPubMed
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, 957–972.CrossRefGoogle ScholarPubMed
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, 151–161.CrossRefGoogle ScholarPubMed
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, 21–30.CrossRefGoogle ScholarPubMed
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, 4866–4872.CrossRefGoogle Scholar
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, 1298–1306.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 1741–1748.CrossRefGoogle ScholarPubMed
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, 2065–2069.CrossRefGoogle ScholarPubMed
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, 486–487.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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. 414–460. Wiley-VCH, New York, USA.Google Scholar
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, 1771–1777.CrossRefGoogle ScholarPubMed
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, 27–38.CrossRefGoogle ScholarPubMed
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, 52–58.CrossRefGoogle ScholarPubMed
Vial, H. J. and Gorenflot, A. (2006). Chemotherapy against babesiosis. Veterinary Parasitology 138, 147–160.CrossRefGoogle ScholarPubMed
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, 1985–1994.CrossRefGoogle Scholar
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, 2067–2075.CrossRefGoogle Scholar
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, 2507–2516.CrossRefGoogle ScholarPubMed
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, 4674–4683.CrossRefGoogle ScholarPubMed
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, 145–149.CrossRefGoogle ScholarPubMed
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, 4185–4192.CrossRefGoogle ScholarPubMed
Werbovetz, K. A. (2006). Diamidines as antitrypanosomal, antileishmanial and antimalarial agents. Current Opinion in Investigational Drugs 7, 147–157.Google ScholarPubMed
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.), 23331–353. Kluwer Academic Publishers, Dordrecht, the Netherlands.Google Scholar
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, 389–408.CrossRefGoogle ScholarPubMed
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, 999–1014.CrossRefGoogle ScholarPubMed
World Health Organization (2010). Control of the Leishmaniasis. WHO Technical Report Series No. 949. World Health Organization, Geneva, Switzerland.Google Scholar
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, 1689–1695.CrossRefGoogle ScholarPubMed
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, 3690–3699.CrossRefGoogle ScholarPubMed