Optimized Ebselen-Based Inhibitors of Bacterial Ureases with Nontypical Mode of Action

Screening of 25 analogs of Ebselen, diversified at the
N-aromatic
residue, led to the identification of the most potent inhibitors of Sporosarcina pasteurii urease reported to date. The
presence of a dihalogenated phenyl ring caused exceptional activity
of these 1,2-benzisoselenazol-3(2H)-ones, with Ki value in a low picomolar range (<20 pM).
The affinity was attributed to the increased π–π
and π–cation interactions of the dihalogenated phenyl
ring with αHis323 and αArg339 during the initial step
of binding. Complementary biological studies with selected compounds
on the inhibition of ureolysis in whole Proteus mirabilis cells showed a very good potency (IC50 < 25 nM in
phosphate-buffered saline (PBS) buffer and IC90 < 50
nM in a urine model) for monosubstituted N-phenyl derivatives. The
crystal structure of S. pasteurii urease
inhibited by one of the most active analogs revealed the recurrent
selenation of the Cys322 thiolate, yielding an unprecedented Cys322-S–Se–Se
chemical moiety.