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The efficacy of novel arylimidamides against Trypanosoma cruzi in vitro

Abstract
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.

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*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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F. I. Apted (1980). Present status of chemotherapy and chemoprophylaxis of human trypanosomiasis in the Eastern Hemisphere. Pharmacology & Therapeutics 11, 391413.

D. da G. Batista , M. M. Batista , G. M. de Oliveira , P. B. do Amaral , J. Lannes-Vieira , C. C. Britto , A. Junqueira , M. M. Lima , A. J. Romanha , P. A. Sales Junior , C. E. Stephens , D. W. Boykin and M.de N. Soeiro (2010). Arylimidamide DB766, a potential chemotherapeutic candidate for Chagas' disease treatment. Antimicrobial Agents and Chemotherapy 54, 29402952.

C. A. Bell , M. Cory , T. A. Fairley , J. E. Hall and R. R. Tidwell (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.

E. Bettiol , M. Samanovic , A. S. Murkin , J. Raper , F. Buckner and A. Rodriguez (2009). Identification of three classes of heteroaromatic compounds with activity against intracellular Trypanosoma cruzi by chemical library screening. PLoS Neglected Tropical Diseases 3, e384.

A. D. Bryceson , J. D. Chulay , M. Mugambi , J. B. Were , G. Gachihi , C. N. Chunge , R. Muigai , S. M. Bhatt , M. Ho , H. C. Spencer , J. Meme and G. Anabwani (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, 705714.

I. S. Caldas , A. Talvani , S. Caldas , C. M. Carneiro , M. de Lana , P. M. da Matta Guedes and M. T. Bahia (2008). Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions. Parasitology Research 103, 413–21.

J. Clayton (2010). Chagas disease: pushing through the pipeline. Nature, London S12S15.

J. R. Coura and P. A. Viñas (2010). Chagas disease: a new worldwide challenge. Nature Outlooks 465 (7301 suppl), S6S7.

C. F. da Silva , M. M. Batista , D.da G. Batista , E. M. de Souza , P. B. da Silva , G. M. de Oliveira , A. S. Meuser , A. R. Shareef , D. W. Boykin and M. de N. Soeiro (2008). In vitro and in vivo studies of the trypanocidal activity of a diarylthiophene diamidine against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 52, 33073314.

A. Daliry , P. B. Da Silva , C. F. Da Silva , M. M. Batista , S. L. De Castro , R. R. Tidwell and M. de N. Soeiro (2009). In vitro analyses of the effect of aromatic diamidines upon Trypanosoma cruzi. Jounal of Antimicrobial Chemotherapy 64, 747750.

H. P. de Koning (2001). Transporters in African trypanosomes: role in drug action and resistance. International Journal for Parasitology 31, 512522.

E. M. De Souza , P. B. da Silva , A. S. Nefertiti , M. A. Ismail , R. K. Arafa , B. Tao , C. K. Nixon-Smith , D. W. Boykin and M. N. Soeiro (2011). Trypanocidal activity and selectivity in vitro of aromatic amidine compounds upon bloodstream and intracellular forms of Trypanosoma cruzi. Experimental Parasitology 127, 429435.

E. M. De Souza , A. Lansiaux , C. Bailly , W. D. Wilson , Q. Hu , D. W. Boykin , M. M. Batista , T. C. Araújo-Jorge and M. N. Soeiro (2004). Phenyl substitution of furamidine markedly potentiates its antiparasitic activity against Trypanosoma cruzi and Leishmania amazonensis. Biochemical Pharmacology 68, 593600.

E. M. De Souza , A. S. Nefertiti , C. Bailly , A. Lansiaux and M. N. Soeiro (2010). Differential apoptosis-like cell death in amastigote and trypomastigote forms from Trypanosoma cruzi-infected heart cells in vitro. Cell and Tissue Research 341, 173180.

E. M. De Souza , G. M. Oliveira , D. W. Boykin , A. Kumar , Q. Hu and M. N. C. Soeiro (2006). Trypanocidal activity of the phenyl-substituted analogue of furamidine DB569 against Trypanosoma cruzi infection in vivo. Journal of Antimicrobial Chemotherapy 58, 610614.

A. A. Farahat , E. Paliakov , A. Kumar , A. E. Barghash , F. E. Goda , H. M. Eisa , T. Wenzler , R. Brun , Y. Liu , W. D. Wilson and D. W. Boykin (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, 21562167.

I. Francesconi , W. D. Wilson , F. A. Tanious , J. E. Hall , B. C. Bender , R. R. Tidwell , D. McCurdy and D. W. Boykin (1999). 2,4-Diphenyl furan diamidines as novel anti-Pneumocystis carinii pneumonia agents. Journal of Medicinal Chemistry 42, 22602265.

L. Hu , R. K. Arafa , M. A. Ismail , A. Patel , M. Munde , W. D. Wilson , T. Wenzler , R. Brun and D. W. Boykin (2009). Synthesis and activity of azaterphenyl diamidines against Trypanosoma brucei rhodesiense and Plasmodium falciparum. Bioorganic & Medicinal Chemistry 17, 66516658.

S. Y. Kim , A. A. Dabb , D. J. Glenn , K. M. Snyder , M. K. Chuk and D. M. Loeb (2008). Intravenous pentamidine is effective as second line Pneumocystis pneumonia prophylaxis in pediatric oncology patients. Pediatric Blood & Cancer 50, 779783.

C. A. Lanteri , M. L. Stewart , J. M. Brock , V. P. Alibu , S. R. Meshnick , R. R. Tidwell and M. P. Barrett (2006). Roles for the Trypanosoma brucei P2 transporter in DB75 uptake and resistance. Molecular Pharmacology 70,15851592.

D. S. Lindsay , B. L. Blagburn , J. E. Hall and R. R. Tidwell (1991). Activity of pentamidine and pentamidine analogs against Toxoplasma gondii in cell cultures. Antimicrobial Agents and Chemotherapy 35,19141916.

F. S. Machado , H. B. Tanowitz and M. M. Teixeira (2010). New drugs for neglected infectious diseases: Chagas' disease. British Journal of Pharmacology 160, 258259.

A. M. Mathis , J. L. Holman , L. M. Sturk , M. A. Ismail , D. W. Boykin , R. R. Tidwell and J. E. Hall (2006). Accumulation and intracellular distribution of antitrypanosomal diamidine compounds DB75 and DB820 in African trypanosomes. Antimicrobial Agents and Chemotherapy 50, 21852191.

A. M. Mathis , A. S. Bridges , M. A. Ismail , A. Kumar , I. Francesconi , M. Anbazhagan , Q. Hu , F. A. Tanious , T. Wenzler , J. Saulter , W. D. Wilson , R. Brun , D. W. Boykin , R. R. Tidwell and J. E. Hall (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.

S. Mazur , F. A. Tanious , D. Ding , A. Kumar , D. W. Boykin , I. J. Simpson , S. Neidle and W. D. Wilson (2000). A thermodynamic and structural analysis of DNA minor-groove complex formation. Journal of Molecular Biology 300, 321337.

M. G. Pacheco , C. F. da Silva , E. M. de Souza , M. M. Batista , P. B. da Silva , A. Kumar , C. E. Stephens , D. W. Boykin and M. de N. Soeiro (2009). Trypanosoma cruzi: activity of heterocyclic cationic molecules in vitro. Experimental Parasitology 123, 7380.

A. E. Purfield , R. R. Tidwell and S. R. Meshnick (2009). The diamidine DB75 targets the nucleus of Plasmodium falciparum. Malaria Journal 8, 19.

A. Rassi Jr., A. Rassi and J. A. Marin-Neto (2010). Chagas disease. Lancet 375, 13881402.

M. O. Rocha , M. M. Teixeira and A. L. Ribeiro (2007). An update on the management of Chagas cardiomyopathy. Expert Review of Anti-Infective Therapy 5, 727743.

J. Rodriques Coura and S. L. de Castro (2002). A critical review on Chagas disease chemotherapy. Memórias do Instituto Oswaldo Cruz 97, 324.

A. C. Rosypal , R. R. Tidwell and D. S. Lindsay (2007). Prevalence of antibodies to Leishmania infantum and Trypanosoma cruzi in wild canids from South Carolina. Journal of Parasitology 93, 955957.

A. C. Rosypal , K. A. Werbovetz , M. Salem , C. E. Stephens , A. Kumar , J. E. Hall and R. R. Tidwell (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, 743749.

C. F. Silva , M. M. Batista , R. A. Mota , E. M. de Souza , C. E. Stephens , P. Som , D. W. Boykin and M. de N. Soeiro (2007 a). Activity of “reversed” diamidines against Trypanosoma cruzi “in vitro. Biochemical Pharmacology 73, 19391946.

C. F. Silva , M. B. Meuser , E. M. De Souza , M. N. Meirelles , C. E. Stephens , P. Som , D. W. Boykin and M. N. Soeiro (2007 b). Cellular effects of reversed amidines on Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 51, 38033809.

M. N. Soeiro and S. L. de Castro (2009). Trypanosoma cruzi targets for new chemotherapeutic approaches. Expert Opinion Therapy Targets 13, 105121.

M. De N. Soeiro and S. L. de Castro (2011). Screening of potential anti-Trypanosoma cruzi candidates: in vitro and in vivo studies. Open Medicinal Chemistry Journal 5, 2130.

M. de N. Soeiro , A. P. Dantas , A. Daliry , C. F. Silva , D. G. Batista , E. M. de Souza , G. M. Oliveira , K. Salomão , M. M. Batista , M. G. Pacheco , P. B. Silva , R. M. Santa-Rita , R. F. Barreto , D. W. Boykin and S. L. Castro (2009). Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies. Memórias do Instituto Oswaldo Cruz 104, 301310.

M. N. Soeiro , E. M. De Souza , C. E. Stephens and D. W. Boykin (2005). Aromatic diamidines as antiparasitic agents. Expert Opinion on Investigational Drugs 14, 957972.

C. E. Stephens , R. Brun , M. M. Salem , K. A. Werbovetz , F. Tanious , W. D. Wilson and D. W. Boykin (2003). The activity of diguanidino and “reversed” diamidino 2,5-diarylfurans versus Trypanosoma cruzi and Leishmania donovani. Bioorganic & Medicinal Chemistry Letters 13, 20652069.

L. Wang , C. Bailly , A. Kumar , D. Ding , M. Bajic , D. W. Boykin and W. D. Wilson (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, 1216.

M. Z. Wang , X. Zhu , A. Srivastava , Q. Liu , J. M. Sweat , T. Pandharkar , C. E. Stephens , E. Riccio , T. Parman , M. Munde , S. Mandal , R. Madhubala , R. R. Tidwell , W. D. Wilson , D. W. Boykin , J. E. Hall , D. E. Kyle and K. A. Werbovetz (2010). Novel arylimidamides for treatment of visceral leishmaniasis. Antimicrobial Agents and Chemotherapy 54, 25072516.

T. Wenzler , D. W. Boykin , M. A. Ismail , J. E. Hall , R. R. Tidwell and R. Brun (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.

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Parasitology
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