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KMID : 0043320120350030469
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Archives of Pharmacal Research
2012 Volume.35 No. 3 p.469 ~ p.479
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Synthesis and evaluation of peptidyl α,β-unsaturated carbonyl derivatives as anti-malarial calpain inhibitors
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Mallik Shyam Kumar
Li Da Yu
Cui Minghua
Song Hyun-Ok
Park Hyun
Kim Hak-Sung
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Abstract
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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.
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KEYWORD
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Malarial calpain, Calpain inhibitor, Dipeptidyl α, β-unsaturated carbonyl derivatives, Michael addition
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