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The efficacy of novel arylimidamides against Trypanosoma cruzi in vitro

Published online by Cambridge University Press:  09 September 2011

CRISTIANE FRANÇA DA SILVA ,
ANISSA DALIRY ,
PATRÍCIA BERNARDINO DA SILVA ,
SENOL AKAY ,
MOLOY BANERJEE ,
ABDELBASSET A. FARAHAT ,
MARY K. FISHER ,
LAIXING HU ,
ARVIND KUMAR  and
ZONGYING LIU
...Show all authors
CRISTIANE FRANÇA DA SILVA
Affiliation:
Laboratório de Biologia Celular, Maria de Nazaré Correia Soeiro, Av. Brasil, 4365. Manguinhos, Rio de Janeiro, RJ, Brazil
ANISSA DALIRY
Affiliation:
Laboratório de Biologia Celular, Maria de Nazaré Correia Soeiro, Av. Brasil, 4365. Manguinhos, Rio de Janeiro, RJ, Brazil
PATRÍCIA BERNARDINO DA SILVA
Affiliation:
Laboratório de Biologia Celular, Maria de Nazaré Correia Soeiro, Av. Brasil, 4365. Manguinhos, Rio de Janeiro, RJ, Brazil
SENOL AKAY
Affiliation:
Department of Chemistry, Augusta State University, Augusta, Georgia, USA
MOLOY BANERJEE
Affiliation:
Department of Chemistry, Augusta State University, Augusta, Georgia, USA
ABDELBASSET A. FARAHAT
Affiliation:
Department of Chemistry, Augusta State University, Augusta, Georgia, USA
MARY K. FISHER
Affiliation:
Department of Chemistry and Physics, Augusta State University, Augusta, Georgia, USA
LAIXING HU
Affiliation:
Department of Chemistry, Augusta State University, Augusta, Georgia, USA
ARVIND KUMAR
Affiliation:
Department of Chemistry, Augusta State University, Augusta, Georgia, USA
ZONGYING LIU
Affiliation:
Department of Chemistry, Augusta State University, Augusta, Georgia, USA
CHAD E. STEPHENS
Affiliation:
Department of Chemistry and Physics, Augusta State University, Augusta, Georgia, USA
DAVID W. BOYKIN
Affiliation:
Department of Chemistry, Augusta State University, Augusta, Georgia, USA
MARIA DE NAZARÉ CORREIA SOEIRO*
Affiliation:
Laboratório de Biologia Celular, Maria de Nazaré Correia Soeiro, Av. Brasil, 4365. Manguinhos, Rio de Janeiro, RJ, Brazil
*
*Corresponding author: Laboratório de Biologia Celular, Maria de Nazaré Correia Soeiro, Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, Brazil. Tel: +055 21 25621368. Fax: +055 21 2562-1432. E-mail: soeiro@ioc.fiocruz.br
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Summary

The present study aimed to determine the in vitro biological efficacy and selectivity of 7 novel AIAs upon bloodstream trypomastigotes and intracellular amastigotes of Trypanosoma cruzi. The biological activity of these aromatic compounds was assayed for 48 and 24 h against intracellular parasites and bloodstream forms of T. cruzi (Y strain), respectively. Additional assays were also performed to determine their potential use in blood banks by treating the bloodstream parasites with the compounds diluted in mouse blood for 24 h at 4°C. Toxicity against mammalian cells was evaluated using primary cultures of cardiac cells incubated for 24 and 48 h with the AIAs and then cellular death rates were determined by MTT colorimetric assays. Our data demonstrated the outstanding trypanocidal effect of AIAs against T. cruzi, especially DB1853, DB1862, DB1867 and DB1868, giving IC50 values ranging between 16 and 70 nanomolar against both parasite forms. All AIAs presented superior efficacy to benznidazole and some, such as DB1868, also demonstrated promising activity as a candidate agent for blood prophylaxis. The excellent anti-trypanosomal efficacy of these novel AIAs against T. cruzi stimulates further in vivo studies and justifies the screening of new analogues with the goal of establishing a useful alternative therapy for Chagas disease.

Keywords

Trypanosoma cruziChagas diseasechemotherapyarylimidamides
Type
Research Article
Information
Parasitology , Volume 138 , Issue 14 , December 2011 , pp. 1863 - 1869
Copyright
Copyright © Cambridge University Press 2011

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References

REFERENCES

Apted, F. I. (1980). Present status of chemotherapy and chemoprophylaxis of human trypanosomiasis in the Eastern Hemisphere. Pharmacology & Therapeutics 11, 391–413.CrossRefGoogle Scholar
Bailly, C., Dassonneville, L., Carrasco, C., Lucas, D., Kumar, A., Boykin, D. W. and Wilson, W. D. (1999). Relationships between topoisomerase II inhibition, sequence-specificity and DNA binding mode of dicationic diphenylfuran derivatives. Anti-Cancer Drug Design 14, 47–60.Google ScholarPubMed
Batista, D. da G., Batista, M. M., de Oliveira, G. M., do 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.de N. (2010). Arylimidamide DB766, a potential chemotherapeutic candidate for Chagas' disease treatment. Antimicrobial Agents and Chemotherapy 54, 2940–2952.CrossRefGoogle ScholarPubMed
Bell, C. A., Cory, M., Fairley, T. A., Hall, J. E. and Tidwell, R. R. (1991). Structure-activity relationships of pentamidine analogs against Giardia lamblia and correlation of antigiardial activity with DNA-binding affinity. Antimicrobial Agents and Chemotherapy 35,1099–107.CrossRefGoogle ScholarPubMed
Bettiol, E., Samanovic, M., Murkin, A. S., Raper, J., Buckner, F. and Rodriguez, A. (2009). Identification of three classes of heteroaromatic compounds with activity against intracellular Trypanosoma cruzi by chemical library screening. PLoS Neglected Tropical Diseases 3, e384.CrossRefGoogle ScholarPubMed
Bryceson, A. D., Chulay, J. D., Mugambi, M., Were, J. B., Gachihi, G., Chunge, C. N., Muigai, R., Bhatt, S. M., Ho, M., Spencer, H. C., Meme, J. and Anabwani, G. (1985). Visceral leishmaniasis unresponsive to antimonial drugs. II. Response to high dosage sodium stibogluconate or prolonged treatment with pentamidine. Transactions of the Royal Society of Tropical Medicine and Hygiene 79, 705–714.CrossRefGoogle ScholarPubMed
Caldas, I. S., Talvani, A., Caldas, S., Carneiro, C. M., de Lana, M., da Matta Guedes, P. M. and Bahia, M. T. (2008). Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions. Parasitology Research 103, 413–21.CrossRefGoogle Scholar
Clayton, J. (2010). Chagas disease: pushing through the pipeline. Nature, London S12–S15.CrossRefGoogle ScholarPubMed
Coura, J. R. and Viñas, P. A. (2010). Chagas disease: a new worldwide challenge. Nature Outlooks 465 (7301 suppl), S6–S7.CrossRefGoogle ScholarPubMed
da Silva, C. F., Batista, M. M., Batista, D.da 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. de N. (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., da Silva, P. B., Batista, M. M., Daliry, A., Tidwell, R. R. and Soeiro, M. de N. (2010). The biological in vitro effect and selectivity of aromatic dicationic compounds on Trypanosoma cruzi. Memorias do Instituto Oswaldo Cruz 105, 239–245.CrossRefGoogle ScholarPubMed
Daliry, A., Da Silva, P. B., Da Silva, C. F., Batista, M. M., De Castro, S. L., Tidwell, R. R. and Soeiro, M. de N. (2009). In vitro analyses of the effect of aromatic diamidines upon Trypanosoma cruzi. Jounal of Antimicrobial Chemotherapy 64, 747–750.CrossRefGoogle ScholarPubMed
de Koning, H. P. (2001). Transporters in African trypanosomes: role in drug action and resistance. International Journal for Parasitology 31, 512–522.CrossRefGoogle ScholarPubMed
De Souza, E. M., da Silva, P. B., Nefertiti, A. S., Ismail, M. A., Arafa, R. K., Tao, B., Nixon-Smith, C. K., Boykin, D. W. and Soeiro, M. N. (2011). Trypanocidal activity and selectivity in vitro of aromatic amidine compounds upon bloodstream and intracellular forms of Trypanosoma cruzi. Experimental Parasitology 127, 429–435.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. (2004). Phenyl substitution of furamidine markedly potentiates its antiparasitic activity against Trypanosoma cruzi and Leishmania amazonensis. Biochemical Pharmacology 68, 593–600.CrossRefGoogle ScholarPubMed
De Souza, E. M., Nefertiti, A. S., Bailly, C., Lansiaux, A. and Soeiro, M. N. (2010). Differential apoptosis-like cell death in amastigote and trypomastigote forms from Trypanosoma cruzi-infected heart cells in vitro. Cell and Tissue Research 341, 173–180.CrossRefGoogle ScholarPubMed
De Souza, E. M., Oliveira, G. M., Boykin, D. W., Kumar, A., Hu, Q. and Soeiro, M. N. C. (2006). Trypanocidal activity of the phenyl-substituted analogue of furamidine DB569 against Trypanosoma cruzi infection in vivo. Journal of Antimicrobial Chemotherapy 58, 610–614.CrossRefGoogle ScholarPubMed
Farahat, A. A., Paliakov, E., Kumar, A., Barghash, A. E., Goda, F. E., Eisa, H. M., Wenzler, T., Brun, R., 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 & Medicinal Chemistry 19, 2156–2167.CrossRefGoogle ScholarPubMed
Francesconi, I., Wilson, W. D., Tanious, F. A., Hall, J. E., Bender, B. C., Tidwell, R. R., McCurdy, D. and Boykin, D. W. (1999). 2,4-Diphenyl furan diamidines as novel anti-Pneumocystis carinii pneumonia agents. Journal of Medicinal Chemistry 42, 2260–2265.CrossRefGoogle Scholar
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 rhodesiense and Plasmodium falciparum. Bioorganic & Medicinal Chemistry 17, 6651–6658.CrossRefGoogle ScholarPubMed
Kim, S. Y., Dabb, A. A., Glenn, D. J., Snyder, K. M., Chuk, M. K. and Loeb, D. M. (2008). Intravenous pentamidine is effective as second line Pneumocystis pneumonia prophylaxis in pediatric oncology patients. Pediatric Blood & Cancer 50, 779–783.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
Laranja, F. S., Dias, E. and Nobrega, G. (1951). Clinical aspect and treatment of Chagas' disease. Prensa Medicine Argentina 38, 465–484.Google 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
Machado, F. S., Tanowitz, H. B. and Teixeira, M. M. (2010). New drugs for neglected infectious diseases: Chagas' disease. British Journal of Pharmacology 160, 258–259.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
Mazur, S., Tanious, F. A., Ding, D., Kumar, A., Boykin, D. W., Simpson, I. J., Neidle, S. and Wilson, W. D. (2000). A thermodynamic and structural analysis of DNA minor-groove complex formation. Journal of Molecular Biology 300, 321–337.CrossRefGoogle ScholarPubMed
Meirelles, M. N., Araujo-Jorge, T. C., Miranda, C. F., De Souza, W. and Barbosa, H. S. (1986). Interaction of Trypanosoma cruzi with heart muscle cells: ultrastructural and cytochemical analysis of endocytic vacuole formation and effect upon myogenesis in vitro. European Journal of Cell Biology 41, 198–206.Google 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. de N. (2009). Trypanosoma cruzi: activity of heterocyclic cationic molecules in vitro. Experimental Parasitology 123, 73–80.CrossRefGoogle ScholarPubMed
Purfield, A. E., Tidwell, R. R. and Meshnick, S. R. (2009). The diamidine DB75 targets the nucleus of Plasmodium falciparum. Malaria Journal 8, 1–9.CrossRefGoogle ScholarPubMed
Rassi, A. Jr., Rassi, A. and Marin-Neto, J. A. (2010). Chagas disease. Lancet 375, 1388–1402.CrossRefGoogle ScholarPubMed
Rocha, M. O., Teixeira, M. M. and Ribeiro, A. L. (2007). An update on the management of Chagas cardiomyopathy. Expert Review of Anti-Infective Therapy 5, 727–743.CrossRefGoogle ScholarPubMed
Rodriques Coura, J. and de Castro, S. L. (2002). A critical review on Chagas disease chemotherapy. Memórias do Instituto Oswaldo Cruz 97, 3–24.CrossRefGoogle ScholarPubMed
Rosypal, A. C., Tidwell, R. R. and Lindsay, D. S. (2007). Prevalence of antibodies to Leishmania infantum and Trypanosoma cruzi in wild canids from South Carolina. Journal of Parasitology 93, 955–957.CrossRefGoogle ScholarPubMed
Rosypal, A. C., Werbovetz, K. A., Salem, M., Stephens, C. E., Kumar, A., Hall, J. E. and Tidwell, R. R. (2008). Inhibition by Dications of in vitro growth of Leishmania major and Leishmania tropica: causative agents of old world cutaneous leishmaniasis. Journal of Parasitology 94, 743–749.CrossRefGoogle ScholarPubMed
Silva, C. F., Batista, M. M., Mota, R. A., de Souza, E. M., Stephens, C. E., Som, P., Boykin, D. W. and Soeiro, M. de N. (2007 a). Activity of “reversed” diamidines against Trypanosoma cruzi “in vitro”. Biochemical Pharmacology 73, 1939–1946.CrossRefGoogle ScholarPubMed
Silva, C. F., Meuser, M. B., De Souza, E. M., Meirelles, M. N., Stephens, C. E., Som, P., Boykin, D. W. and Soeiro, M. N. (2007 b). Cellular effects of reversed amidines on Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 51, 3803–3809.CrossRefGoogle ScholarPubMed
Soeiro, M. N. and de Castro, S. L. (2009). Trypanosoma cruzi targets for new chemotherapeutic approaches. Expert Opinion Therapy Targets 13, 105–121.CrossRefGoogle ScholarPubMed
Soeiro, M. De N. 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
Soeiro, M. N. C., Daliry, A., Silva, C. F., Batista, D. G. J., de Souza, E. M., Oliveira, G. M., Salomão, K., Menna-Barreto, R. F. S. and de Castro, S. L. (2010). Electron microscopy approaches for the investigation of the cellular targets of trypanocidal agents in Trypanosoma cruzi In Microscopy: Science, Technology, Applications and Education 1, 191–203. Formatex Research Center, Badajoz, Spain.Google Scholar
Soeiro, M. de N., Dantas, A. P., Daliry, A., Silva, C. F., Batista, D. G., de Souza, E. M., Oliveira, G. M., Salomão, K., Batista, M. M., Pacheco, M. G., Silva, P. B., Santa-Rita, R. M., Barreto, R. F., Boykin, D. W. and Castro, S. L. (2009). Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies. Memórias do Instituto Oswaldo Cruz 104, 301–310.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
Stephens, C. E., Brun, R., Salem, M. M., Werbovetz, K. A., Tanious, F., Wilson, W. D. and Boykin, D. W. (2003). The activity of diguanidino and “reversed” diamidino 2,5-diarylfurans versus Trypanosoma cruzi and Leishmania donovani. Bioorganic & Medicinal Chemistry Letters 13, 2065–2069.CrossRefGoogle ScholarPubMed
Wang, L., Bailly, C., Kumar, A., Ding, D., Bajic, M., Boykin, D. W. and Wilson, W. D. (2000). Specific molecular recognition of mixed nucleic acid sequences: an aromatic dication that binds in the DNA minor groove as a dimer. Proceedings of the National Academy of Sciences, USA 97, 12–16.CrossRefGoogle ScholarPubMed
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 treatment of visceral leishmaniasis. Antimicrobial Agents and Chemotherapy 54, 2507–2516.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. (2006). Diamidines as antitrypanosomal, antileishmanial and antimalarial agents. Current Opinion in Investigational Drugs 7, 147–157.Google ScholarPubMed