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

Abstract

Screening of 25 analogs of Ebselen, diversified at the N-aromatic residue, led to the identification of the most potent inhibitors of <i>Sporosarcina pasteurii</i> urease reported to date. The presence of a dihalogenated phenyl ring caused exceptional activity of these 1,2-benzisoselenazol-3(2<i>H</i>)-ones, with <i>K_i</i> 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 <i>Proteus mirabilis</i> 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 <i>S. pasteurii</i> 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.