title: Synthesis and antiprotozoal activity of 2,5-bis[amidinoaryl]thiazoles.
abstract: Seven novel diamidino 2,5-bis(aryl)thiazoles (5a-g) were synthesized and evaluated against Trypanosoma brucei rhodensiense (T. b. r.) and Plasmodium falciparum (P. f.). The diamidines were obtained directly from the corresponding bis-nitriles (4a-g) by the action of lithium bis(trimethylsilyl)amide. The bis-nitriles 4a-f were synthesized in four steps starting with the Stille coupling of 2-tributyltinthiazole with the appropriate cyanoaryl halide. The bis-nitrile 5g was obtained by the palladium facilitated coupling of the mixed tin-silyl reagent 2-trimethylsilyl-5-trimethyltinthiazole with 2-bromo-5-cyanopyridine. The amidoxime potential prodrugs 6a-e, 6g were obtained by the reaction of hydroxylamine with the bis-nitriles. O-Methylation of the amidoximes gave the corresponding N-methoxyamidines 7a-c, 7e, 7g. The diamidines showed strong DNA binding affinity as reflected by DeltaT(m) measurements. Four of the diamidines 5a, 5b, 5d and 5e were highly active in vitro against P. f. giving IC(50) values between 1.1 and 2.5nM. The same four diamidines showed IC(50) values between 4 and 6nM against T. b. r. The selectivity indices ranged from 233 to 9175. One diamidine 5a produced one of four cures at an ip dose of 4x5mg/kg in the STIB900 mouse model for acute African trypanosomiasis. The amidoxime and N-methoxyamidine of 5a were the only produgs to provide cures (1/4 cures) in the same mouse model on oral dosage at 4x25mg/kg.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303-3083, USA.
authors.forename: Danuta
authors.initials: D
authors.lastname: Branowska
authors.forename: Abdelbasset A
authors.initials: AA
authors.lastname: Farahat
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D016054:DNA, Protozoan / Q000737:chemistry; D004195:Disease Models, Animal; D004355:Drug Stability; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000138:chemical synthesis / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D000962:Antimalarials; D000981:Antiprotozoal Agents; D016054:DNA, Protozoan; D013844:Thiazoles; D014344:Trypanocidal Agents; D010419:Pentamidine
references.citation: Eur J Med Chem. 1996;31(10):767-73
references.pmid: 22026932
references.citation: Biochimie. 2008 Jul;90(7):999-1014
references.pmid: 18343228
references.citation: J Med Chem. 2003 Oct 23;46(22):4761-9
references.pmid: 14561095
references.citation: J Am Chem Soc. 2004 Oct 27;126(42):13659-69
references.pmid: 15493923
references.citation: Biopolymers. 1992 Sep;32(9):1201-14
references.pmid: 1420988
references.citation: J Infect Dis. 2005 Jul 15;192(2):319-22
references.pmid: 15962227
references.citation: Curr Opin Investig Drugs. 2006 Feb;7(2):147-57
references.pmid: 16499285
references.citation: Acta Trop. 2008 Oct;108(1):6-10
references.pmid: 18722336
references.citation: Adv Parasitol. 2006;63:125-83
references.pmid: 17134653
references.citation: Trends Parasitol. 2003 Nov;19(11):488-94
references.pmid: 14580959
references.citation: J Med Chem. 2006 Aug 24;49(17):5324-32
references.pmid: 16913722
references.citation: PLoS Negl Trop Dis. 2009 Aug 25;3(8):e440
references.pmid: 19707561
references.citation: Antimicrob Agents Chemother. 2009 Oct;53(10):4185-92
references.pmid: 19620327
references.citation: Arch Pharm (Weinheim). 2008 Mar;341(3):149-63
references.pmid: 18297679
references.citation: Xenobiotica. 2005 Mar;35(3):211-26
references.pmid: 16019947
references.citation: Nature. 2002 Feb 7;415(6872):686-93
references.pmid: 11832957
references.citation: Curr Med Chem Anticancer Agents. 2005 Jul;5(4):389-408
references.pmid: 16101490
references.citation: J Med Chem. 1980 May;23(5):578-81
references.pmid: 7381860
references.citation: Fundam Clin Pharmacol. 2003 Apr;17(2):171-81
references.pmid: 12667227
references.citation: J Med Chem. 2008 Feb 28;51(4):909-23
references.pmid: 18247550
references.citation: Methods Mol Biol. 1997;90:219-40
references.pmid: 9407538
references.citation: Curr Pharm Des. 2008;14(10):1001-47
references.pmid: 18473852
references.citation: Bioorg Med Chem. 2006 Nov 15;14(22):7434-45
references.pmid: 16889966
references.citation: Trends Parasitol. 2003 Nov;19(11):477-8
references.pmid: 14580957
references.citation: J Med Chem. 1977 Sep;20(9):1219-21
references.pmid: 336890
references.citation: Eur J Med Chem. 1995;30(2):99-106
references.pmid: 21423835
references.citation: Expert Opin Investig Drugs. 2005 Aug;14(8):957-72
references.pmid: 16050790
references.citation: Br J Pharmacol. 2007 Dec;152(8):1155-71
references.pmid: 17618313
references.citation: FEBS Lett. 1996 Feb 12;380(1-2):73-8
references.pmid: 8603750