Cis-Configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2.
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.
Degel
Björn
B
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Staib
Peter
P
Rohrer
Sebastian
S
Scheiber
Josef
J
Martina
Erika
E
Büchold
Christian
C
Baumann
Knut
K
Morschhäuser
Joachim
J
Schirmeister
Tanja
T
D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D000605:Amino Alcohols / Q000737:chemistry / Q000378:metabolism; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001388:Aziridines / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D013237:Stereoisomerism; D013379:Substrate Specificity
D000596:Amino Acids; D000605:Amino Alcohols; D000935:Antifungal Agents; D001388:Aziridines; D015853:Cysteine Proteinase Inhibitors; D004852:Epoxy Compounds; D005656:Fungal Proteins; D016282:Aspartic Acid Endopeptidases; C090753:SAP2 protein, Candida