Synthesis and evaluation of peptidyl α,β-unsaturated carbonyl derivatives as anti-malarial calpain inhibitors

Shyam Kumar Mallik; Da Yu Li; Minghua Cui; Hyun-Ok Song; Hyun Park; Hak Sung Kim

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Synthesis and evaluation of peptidyl α,β-unsaturated carbonyl derivatives as anti-malarial calpain inhibitors

机译：肽基α，β-不饱和羰基衍生物作为抗疟钙蛋白酶抑制剂的合成与评价

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Malarial calpain is a cysteine protease believed to be a central mediator essential for parasitic activities. N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN), a calpain inhibitor, showed an excellent inhibitory effect on the erythrocytic stages of Plasmodium falciparum. However the aldehyde group of ALLN makes it susceptible to metabolism. Therefore, we designed α,β-unsaturated carbonyl peptides that could serve as electrophiles for cysteine residues in calpain. Among the synthetic analogs based on the structure of ALLN, peptidyl esters 7, 8 and 9 showed the most potent anti-malarial effects, with the same IC50 values of 5.0 μM. Also they showed the high selective toxicity for the malaria versus Hela cell with 40.6, 69.2 and 24.3 fold for 7, 8 and 9, respectively. Dipeptidyl α,β-unsaturated carbonyl derivatives consisting of two amino acids gave better anti-malarial effects than those consisting with one amino acid. The fluctuation in anti-malarial activity with small changes in chemical structure indicates the possibilities of improving synthetic analogs.

机译：疟疾钙蛋白酶是一种半胱氨酸蛋白酶，被认为是寄生虫活动必不可少的中心介质。钙蛋白酶抑制剂N-乙酰基-L-亮氨酰-L-亮氨酰-L-净核苷（ALLN）对恶性疟原虫的红细胞阶段显示出优异的抑制作用。然而，ALLN的醛基使其易于代谢。因此，我们设计了可以用作钙蛋白酶中半胱氨酸残基亲电试剂的α，β-不饱和羰基肽。在基于ALLN结构的合成类似物中，肽基酯7、8和9显示出最有效的抗疟疾作用，IC50值为5.0μM。他们还显示出对疟疾与Hela细胞的高选择性毒性，分别为7、8和9的40.6、69.2和24.3倍。由两个氨基酸组成的二肽基α，β-不饱和羰基衍生物比由一个氨基酸组成的那些具有更好的抗疟作用。化学结构上的微小变化引起的抗疟疾活性的波动表明改进合成类似物的可能性。

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《Archives of Pharmacal Research》 |2012年第3期|p.469-479|共11页
作者
Shyam Kumar Mallik; Da Yu Li; Minghua Cui; Hyun-Ok Song; Hyun Park; Hak Sung Kim;
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Malarial calpain – Calpain inhibitor – Dipeptidyl α,β; unsaturated carbonyl derivatives – Michael addition;

机译：疟疾钙蛋白酶–钙蛋白酶抑制剂–二肽基α;β;不饱和羰基衍生物–迈克尔加成;

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1. Synthesis and evaluation of peptidyl α,β-unsaturated carbonyl derivatives as anti-malarial calpain inhibitors. [J] . Shyam Kumar Mallik, Da Yu Li, Minghua Cui, Archives of pharmacal research . 2012,第3期

机译：肽基α，β-不饱和羰基衍生物的合成和评价作为抗疟钙蛋白酶抑制剂。
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Synthesis and evaluation of peptidyl α,β-unsaturated carbonyl derivatives as anti-malarial calpain inhibitors

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