title: Arylimidamide DB766, a potential chemotherapeutic candidate for Chagas' disease treatment.
abstract: Chagas' disease, a neglected tropical illness for which current therapy is unsatisfactory, is caused by the intracellular parasite Trypanosoma cruzi. The goal of this work is to investigate the in vitro and in vivo effects of the arylimidamide (AIA) DB766 against T. cruzi. This arylimidamide exhibits strong trypanocidal activity and excellent selectivity for bloodstream trypomastigotes and intracellular amastigotes (Y strain), giving IC(50)s (drug concentrations that reduce 50% of the number of the treated parasites) of 60 and 25 nM, respectively. DB766 also exerts striking effects upon different parasite stocks, including those naturally resistant to benznidazole, and displays higher activity in vitro than the reference drugs. By fluorescent and transmission electron microscopy analyses, we found that this AIA localizes in DNA-enriched compartments and induces considerable damage to the mitochondria. DB766 effectively reduces the parasite load in the blood and cardiac tissue and presents efficacy similar to that of benznidazole in mouse models of T. cruzi infection employing the Y and Colombian strains, using oral and intraperitoneal doses of up to 100 mg/kg/day that were given after the establishment of parasite infection. This AIA ameliorates electrocardiographic alterations, reduces hepatic and heart lesions induced by the infection, and provides 90 to 100% protection against mortality, which is similar to that provided by benznidazole. Our data clearly show the trypanocidal efficacy of DB766, suggesting that this AIA may represent a new lead compound candidate to Chagas' disease treatment.
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Denise da Gama Jaén
authors.initials: Dda G
authors.lastname: Batista
authors.forename: Marcos Meuser
authors.initials: MM
authors.lastname: Batista
authors.forename: Gabriel Melo
authors.initials: GM
authors.lastname: de Oliveira
authors.forename: Patrícia Borges
authors.initials: PB
authors.lastname: do Amaral
authors.forename: Joseli
authors.initials: J
authors.lastname: Lannes-Vieira
authors.forename: Constança Carvalho
authors.initials: CC
authors.lastname: Britto
authors.forename: Angela
authors.initials: A
authors.lastname: Junqueira
authors.forename: Marli Maria
authors.initials: MM
authors.lastname: Lima
authors.forename: Alvaro José
authors.initials: AJ
authors.lastname: Romanha
authors.forename: Policarpo Ademar
authors.initials: PA
authors.lastname: Sales Junior
authors.forename: Chad E
authors.initials: CE
authors.lastname: Stephens
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: Maria de Nazaré Correia
authors.initials: Mde N
authors.lastname: Soeiro
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D004562:Electrocardiography; D005260:Female; D005663:Furans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure
chemical_list: C552046:2,5-bis(2-(2-propoxy)-4-(2-pyridylimino)aminophenyl)furan; D000578:Amidines; D005663:Furans; D014344:Trypanocidal Agents
references.citation: Eur Heart J. 2008 Nov;29(21):2587-91
references.pmid: 18840880
references.citation: J Med Chem. 1990 Apr;33(4):1252-7
references.pmid: 2319567
references.citation: FEMS Microbiol Rev. 2005 Nov;29(5):987-1020
references.pmid: 16040150
references.citation: Antimicrob Agents Chemother. 1998 Mar;42(3):666-74
references.pmid: 9517949
references.citation: Antimicrob Agents Chemother. 2008 Sep;52(9):3307-14
references.pmid: 18625779
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:41-5
references.pmid: 19753456
references.citation: Mem Inst Oswaldo Cruz. 1989 Apr-Jun;84(2):237-40
references.pmid: 2517566
references.citation: Ann Intern Med. 2006 May 16;144(10):724-34
references.pmid: 16702588
references.citation: Antimicrob Agents Chemother. 2007 Aug;51(8):2801-10
references.pmid: 17517831
references.citation: Biochem Pharmacol. 2004 Aug 15;68(4):593-600
references.pmid: 15276066
references.citation: Evid Based Complement Alternat Med. 2011;2011:185918
references.pmid: 19213854
references.citation: Trans R Soc Trop Med Hyg. 1987;81(5):755-9
references.pmid: 3130683
references.citation: Am J Trop Med Hyg. 1994 Dec;51(6):771-7
references.pmid: 7810810
references.citation: Braz J Med Biol Res. 1993 Nov;26(11):1219-29
references.pmid: 8136722
references.citation: Ann Trop Med Parasitol. 1977 Jun;71(2):157-66
references.pmid: 869606
references.citation: J Antimicrob Chemother. 2009 Oct;64(4):747-50
references.pmid: 19671588
references.citation: Circulation. 2007 Mar 6;115(9):1109-23
references.pmid: 17339569
references.citation: Biochimie. 2008 Jul;90(7):999-1014
references.pmid: 18343228
references.citation: Mem Inst Oswaldo Cruz. 1993 Jan-Mar;88(1):171-2
references.pmid: 8246754
references.citation: Mem Inst Oswaldo Cruz. 2002 Jan;97(1):3-24
references.pmid: 11992141
references.citation: Biochem J. 1996 Apr 15;315 ( Pt 2):631-4
references.pmid: 8615840
references.citation: Trans R Soc Trop Med Hyg. 1987;81(3):415-9
references.pmid: 3120367
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:263-9
references.pmid: 19753483
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:301-10
references.pmid: 19753489
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Mem Inst Oswaldo Cruz. 2004 Nov;99(7):697-701
references.pmid: 15654424
references.citation: Parasitology. 2010 Feb;137(2):251-9
references.pmid: 19765349
references.citation: Postgrad Med J. 2006 Dec;82(974):788-98
references.pmid: 17148699
references.citation: Eur J Cell Biol. 1986 Aug;41(2):198-206
references.pmid: 3093234
references.citation: Microbes Infect. 2001 Oct;3(12):971-84
references.pmid: 11580984
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:89-100
references.pmid: 19753463
references.citation: Nat Rev Drug Discov. 2006 Nov;5(11):941-55
references.pmid: 17080030
references.citation: J Cell Biochem. 1984;24(4):357-71
references.pmid: 6432804
references.citation: Antimicrob Agents Chemother. 2010 Jun;54(6):2507-16
references.pmid: 20368397
references.citation: Am J Trop Med Hyg. 1984 Mar;33(2):236-8
references.pmid: 6424485
references.citation: J Antimicrob Chemother. 2005 Dec;56(6):1034-41
references.pmid: 16269551
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:311-8
references.pmid: 19753490
references.citation: Rev Inst Med Trop Sao Paulo. 2008 Mar-Apr;50(2):67-74
references.pmid: 18488083
references.citation: Exp Parasitol. 2009 Sep;123(1):73-80
references.pmid: 19520077
references.citation: Ann Trop Med Parasitol. 1982 Feb;76(1):37-43
references.pmid: 7082077
references.citation: Parasite. 1997 Jun;4(2):133-9
references.pmid: 9296058
references.citation: Curr Mol Pharmacol. 2008 Jun;1(2):151-61
references.pmid: 20021429
references.citation: Am J Trop Med Hyg. 2009 Apr;80(4):528-35
references.pmid: 19346370
references.citation: Emerg Infect Dis. 2009 Apr;15(4):653-5
references.pmid: 19331764
references.citation: Drug Target Insights. 2007;2:61-9
references.pmid: 21901063
references.citation: Rev Esp Cardiol. 2007 Mar;60(3):285-93
references.pmid: 17394874
references.citation: Mol Biochem Parasitol. 1999 May 25;100(2):163-72
references.pmid: 10391378
references.citation: J Parasitol. 2008 Jun;94(3):743-9
references.pmid: 18605790
references.citation: Acta Trop. 2008 Oct;108(1):6-10
references.pmid: 18722336
references.citation: Am J Trop Med Hyg. 1998 Jun;58(6):807-11
references.pmid: 9660469
references.citation: Mem Inst Oswaldo Cruz. 2007 Oct 30;102 Suppl 1:47-56
references.pmid: 17891274
references.citation: Biochem Pharmacol. 2007 Jun 15;73(12):1939-46
references.pmid: 17462605
references.citation: Curr Med Chem Anticancer Agents. 2005 Jul;5(4):409-20
references.pmid: 16101491
references.citation: Rev Inst Med Trop Sao Paulo. 1962 Nov-Dec;4:389-96
references.pmid: 14015230
references.citation: Expert Opin Investig Drugs. 2005 Aug;14(8):957-72
references.pmid: 16050790
references.citation: Bioorg Med Chem. 2008 Jan 15;16(2):683-91
references.pmid: 17976993
references.citation: J Parasitol. 1993 Jun;79(3):451-4
references.pmid: 8501607
references.citation: Nat Med. 2008 May;14(5):542-50
references.pmid: 18425131
references.citation: Mem Inst Oswaldo Cruz. 2002 Jul;97(5):603-12
references.pmid: 12219120
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:108-14
references.pmid: 19753465
references.citation: Travel Med Infect Dis. 2008 May;6(3):162-3
references.pmid: 18486077
references.citation: J Antimicrob Chemother. 2006 Sep;58(3):610-4
references.pmid: 16854954
references.citation: Mem Inst Oswaldo Cruz. 2007 Oct 30;102 Suppl 1:11-8
references.pmid: 17891281
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:122-35
references.pmid: 19753467
references.citation: PLoS Negl Trop Dis. 2009;3(2):e384
references.pmid: 19238193
references.citation: Antimicrob Agents Chemother. 2007 Nov;51(11):3803-9
references.pmid: 17698624
references.citation: Expert Opin Ther Targets. 2009 Jan;13(1):105-21
references.pmid: 19063710
references.citation: J Med Chem. 2001 May 24;44(11):1741-8
references.pmid: 11356109
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:226-35
references.pmid: 19753478
references.citation: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:167-80
references.pmid: 19753472
references.citation: Rev Soc Bras Med Trop. 2008 Mar-Apr;41(2):193-6
references.pmid: 18545843