Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense.
- Patrick DA University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB7525, Chapel Hill, NC 27599-7525, USA.
- Wenzler T Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
- Yang S Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA.
- Weiser PT University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB7525, Chapel Hill, NC 27599-7525, USA.
- Wang MZ Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA.
- Brun R Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
- Tidwell RR University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB7525, Chapel Hill, NC 27599-7525, USA. Electronic address: Tidwell@med.unc.edu.
- 2016-04-23
Published in:
- Bioorganic & medicinal chemistry. - 2016
Amide
Antitrypanosomal
Metabolic stability
Thiazole
Urea
Amides
Amines
Animals
Antiprotozoal Agents
Cell Survival
Dose-Response Relationship, Drug
Humans
Mice
Microsomes, Liver
Molecular Structure
Myoblasts
Parasitic Sensitivity Tests
Rats
Structure-Activity Relationship
Thiazoles
Trypanosoma brucei rhodesiense
Urea
English
2-(2-Benzamido)ethyl-4-phenylthiazole (1) was one of 1035 molecules (grouped into 115 distinct scaffolds) found to be inhibitory to Trypanosoma brucei, the pathogen causing human African trypanosomiasis, at concentrations below 3.6μM and non-toxic to mammalian (Huh7) cells in a phenotypic high-throughput screen of a 700,000 compound library performed by the Genomics Institute of the Novartis Research Foundation (GNF). Compound 1 and 72 analogues were synthesized in this lab by one of two general pathways. These plus 10 commercially available analogues were tested against T. brucei rhodesiense STIB900 and L6 rat myoblast cells (for cytotoxicity) in vitro. Forty-four derivatives were more potent than 1, including eight with IC50 values below 100nM. The most potent and most selective for the parasite was the urea analogue 2-(2-piperidin-1-ylamido)ethyl-4-(3-fluorophenyl)thiazole (70, IC50=9nM, SI>18,000). None of 33 compounds tested were able to cure mice infected with the parasite; however, seven compounds caused temporary reductions of parasitemia (⩾97%) but with subsequent relapses. The lack of in vivo efficacy was at least partially due to their poor metabolic stability, as demonstrated by the short half-lives of 15 analogues against mouse and human liver microsomes.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1016/j.bmc.2016.04.006
- PMID 27102161
- Persistent URL
- https://sonar.ch/global/documents/232155
Statistics
Document views: 21
File downloads:
- Full-text: 0