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: Danuta Branowska, Abdelbasset A Farahat, Arvind Kumar, Tanja Wenzler, Reto Brun, Yang Liu, W David Wilson, David W Boykin
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 10 Pg. 3551-8 (May 15 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20403703 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Antimalarials
• Antiprotozoal Agents
• DNA, Protozoan
• Thiazoles
• Trypanocidal Agents
• Pentamidine

Topics

• Administration, Oral
• Animals
• Antimalarials (therapeutic use)
• Antiprotozoal Agents (chemical synthesis, therapeutic use)
• DNA, Protozoan (chemistry)
• Disease Models, Animal
• Drug Stability
• Malaria, Falciparum (drug therapy)
• Mice
• Parasitic Sensitivity Tests
• Pentamidine (chemical synthesis, therapeutic use)
• Plasmodium falciparum (drug effects)
• Rats
• Stereoisomerism
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, therapeutic use)
• Trypanocidal Agents (therapeutic use)
• Trypanosoma brucei brucei (drug effects)
• Trypanosomiasis, African (drug therapy)