期刊
CHEMMEDCHEM
卷 10, 期 9, 页码 1484-1487出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201500204
关键词
dipeptidyl enoates; inhibitors; rhodesain; sleeping sickness; trypanosomiasis
资金
- Generalitat Valenciana under VALi+d Program
- Deutsche Forschungsgemeinschaft (DFG) [SFB630]
Dipeptidyl enoates were prepared through a high-yielding two-step synthetic route. They have a dipeptidic structure with a 4-oxoenoate moiety as a warhead with multiple reactive sites. Dipeptidyl enoates were screened against rhodesain and human cathepsinsB and L, and were found to be potent and selective inhibitors of rhodesain. Among them (S,E)-ethyl 5-((S)-2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanamido)-7-methyl-4-oxooct-2-enoate (6) was the most potent, with an IC50 value of 16.4nM and k(inact)/K-i=1.6x10(6)M(-1)s(-1) against rhodesain. These dipeptidyl enoates display a reversible mode of inhibition at very low concentrations and an irreversible mode at higher concentrations. Inhibition kinetics data, supported by docking studies, suggest a dual mode of action via attack of cysteine thiolate at two reactive positions.
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