期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 22, 页码 5031-5035出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.10.002
关键词
Aldehyde; Covalent inhibitor; Cysteine protease; Nitrile; Oxime; Warhead
资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/18009-4, 2013/01128-0, 2016/10362-5, 2015/14304-7, 2016/0946-5]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [400658-2014-3]
The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the alpha methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude. (C) 2017 Elsevier Ltd. All rights reserved.
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