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 pi-pi and pi-cation interactions of the dihalogenated phenyl ring with alpha His323 and alpha Arg339 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.

Optimized Ebselen-Based Inhibitors of Bacterial Ureases with Nontypical Mode of Action / Macegoniuk, Katarzyna; Tabor, Wojciech; Mazzei, Luca; Cianci, Michele; Giurg, Mirosław; Olech, Kamila; Burda-Grabowska, Małgorzata; Kaleta, Rafał; Grabowiecka, Agnieszka; Mucha, Artur; Ciurli, Stefano; Berlicki, Łukasz. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 66:3(2023), pp. 2054-2063. [10.1021/acs.jmedchem.2c01799]

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

Cianci, Michele
Membro del Collaboration Group
;
2023-01-01

Abstract

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 pi-pi and pi-cation interactions of the dihalogenated phenyl ring with alpha His323 and alpha Arg339 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.
2023
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11566/314592
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 3
  • ???jsp.display-item.citation.isi??? 3
social impact