Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense

Abstract

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 3.6 μM 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 100 nM. 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 = 9 nM, SI > 18,000). None of 33 compounds tested were able to cure mice infected with the parasite; however, six 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.

Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis

“…While piperidyl urea 5 was readily prepared by the reaction of the primary amine 75 and piperidine-1-carbonyl chloride, 14 alternate strategy was required for substituted piperidine ureas 11–19 where the corresponding N -carbonyl chlorides were not readily available. The use of triphosgene to generate these derivatives from substituted piperidines was generally unreliable as the reactions proceeded very slowly and were difficult to monitor in the absence of UV chromophores.…”

“…While a number of the initial analogues 14 were highly potent against the parasite in vitro, they exhibited poor metabolic stability, which precluded their further advancement as drug candidates. The goal of the present study was to improve metabolic stability while maintaining potency.…”

“…Lawesson’s reagent (493 mg, 1.22 mmol) was added to a solution of 2-(2-benzamido)ethyl-4-phenylthiazole ( 1 , 14 353 mg, 1.15 mmol) in THF (20 mL). The mixture was stirred overnight before being diluted with saturated NaHCO 3 solution and extracted into DCM.…”

“…A suspension of 4-phenylthiazol-2-ethylamine hydrobromide ( 74 , 14 500 mg, 1.75 mL) in DCM (8 mL) was treated with Et 3 N (0.6 mL, 4.30 mmol) to give a homogeneous solution. Carbon disulfide (1.2 mL, 19.3 mmol) was added, and the mixture was stirred overnight.…”

Synthesis and biological evaluation of N -cyanoalkyl-, N -aminoalkyl-, and N -guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents

“…Despite this, most research efforts to replenish the antitrypanosomal pipeline remain focussed on the development of novel compounds, rationally designed or screened against one or several parasite biological targets16, 17, 18, 19 or, more often, arising from phenotypic whole cell screens of compound libraries 20, 21, 22, 23, 24, 25, 26…”