Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense.
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.
University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB7525, Chapel Hill, NC 27599-7525, USA.
Donald A
DA
Patrick
Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
Tanja
T
Wenzler
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA.
Sihyung
S
Yang
University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB7525, Chapel Hill, NC 27599-7525, USA.
Patrick T
PT
Weiser
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA.
Michael Zhuo
MZ
Wang
Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
Reto
R
Brun
University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB7525, Chapel Hill, NC 27599-7525, USA. Electronic address: Tidwell@med.unc.edu.
Richard R
RR
Tidwell
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D032446:Myoblasts / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
D000577:Amides; D000588:Amines; D000981:Antiprotozoal Agents; D013844:Thiazoles; D014508:Urea
Amide; Antitrypanosomal; Metabolic stability; Thiazole; Urea