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Cis ‐Configured Aziridines Are New Pseudo‐Irreversible Dual‐Mode Inhibitors of Candida albicans Secreted Aspartic Protease 2
Author(s) -
Degel Björn,
Staib Peter,
Rohrer Sebastian,
Scheiber Josef,
Martina Erika,
Büchold Christian,
Baumann Knut,
Morschhäuser Joachim,
Schirmeister Tanja
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700101
Subject(s) - chemistry , stereochemistry , enzyme , docking (animal) , active site , nucleophile , protease , candida albicans , amino acid , aspartic acid , biochemistry , biology , microbiology and biotechnology , medicine , nursing , catalysis
A series of cis ‐configured epoxides and aziridines containing hydrophobic moieties and amino acid esters were synthesized as new potential inhibitors of the secreted aspartic protease 2 (SAP2) of Candida albicans . Enzyme assays revealed the N ‐benzyl‐3‐phenyl‐substituted aziridines 11 and 17 as the most potent inhibitors, with second‐order inhibition rate constants ( k 2 ) between 56 000 and 121 000 M −1 min −1 . The compounds were shown to be pseudo‐irreversible dual‐mode inhibitors: the intermediate esterified enzyme resulting from nucleophilic ring opening was hydrolyzed and yielded amino alcohols as transition‐state‐mimetic reversible inhibitors. The results of docking studies with the ring‐closed aziridine forms of the inhibitors suggest binding modes mainly dominated by hydrophobic interactions with the S1, S1′, S2, and S2′ subsites of the protease, and docking studies with the processed amino alcohol forms predict additional hydrogen bonds of the new hydroxy group to the active site Asp residues. C. albicans growth assays showed the compounds to decrease SAP2‐dependent growth while not affecting SAP2‐independent growth.