Synthesis and antiprotozoal activity of 2,5-bis[amidinoaryl]thiazoles.
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.
Branowska
Danuta
D
Department of Chemistry, Georgia State University, Atlanta, GA 30303-3083, USA.
Farahat
Abdelbasset A
AA
Kumar
Arvind
A
Wenzler
Tanja
T
Brun
Reto
R
Liu
Yang
Y
Wilson
W David
WD
Boykin
David W
DW
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*
D000962:Antimalarials; D000981:Antiprotozoal Agents; D016054:DNA, Protozoan; D013844:Thiazoles; D014344:Trypanocidal Agents; D010419:Pentamidine
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