- Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense
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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, 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.
- Patrick, Donald A.,Wenzler, Tanja,Yang, Sihyung,Weiser, Patrick T.,Wang, Michael Zhuo,Brun, Reto,Tidwell, Richard R.
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p. 2451 - 2465
(2016/05/19)
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- A convenient synthesis of ethyl 3-aminopropanedithioate (β-alanine ethyl dithioester)
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A five-step sequence allowing the preparation of ethyl 3- aminopropanedithioate from N-(Boc)-β-alanine via the key intermediate N- (Boc)-β-alaninethioacyl-N-phthalimide is described.
- Josse, Olivier,Labar, Daniel,Marchand-Brynaert, Jacqueline
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p. 404 - 406
(2007/10/03)
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- Dithio and thiono esters, LVII: Synthesis of dithio and thiono esters of N-protected β- and γ-amino acids
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The N-protected β-aminonitriles 1 were transformed into the imidoester or thiolimidoester hydrochlorides 2 or 3 according to Pinner and sulfhydrolyzed with H2S to give the N-protected β-amino thiono esters 4 or dithio esters 5. Alkylation of th
- Brutsche,Hartke
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p. 271 - 276
(2007/10/02)
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- Acylation of Dibasic Compounds Containing Amino Amidine and Aminoguanidine Functions
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The site of acylation in difunctional compounds containing an amine and either an amidine or guanidine can be determined from the ultraviolet absorption spectrum of the acylated product.If the amidine or guanidine has been acylated, the product possesses a chromophore that is pH dependent, whereas if an amide was formed, the chromophore is independent of pH.
- Barker, Peter L.,Gendler, Paul L.,Rapoport, Henry
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p. 2455 - 2465
(2007/10/02)
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