title: Synthesis and evaluation of peptidyl α,β-unsaturated carbonyl derivatives as anti-malarial calpain inhibitors.
abstract: 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.
authors.affiliation: College of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Jeonbuk 570-749, Korea.
authors.forename: Shyam Kumar
authors.initials: SK
authors.lastname: Mallik
authors.forename: Da Yu
authors.initials: DY
authors.lastname: Li
authors.forename: Minghua
authors.initials: M
authors.lastname: Cui
authors.forename: Hyun-Ok
authors.initials: HO
authors.lastname: Song
authors.forename: Hyun
authors.initials: H
authors.lastname: Park
authors.forename: Hak Sung
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002845:Chromatography; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D015800:Protozoan Proteins; C063261:acetylleucyl-leucyl-norleucinal; D002154:Calpain