作者: Peng, Peng ; Feng, Kairui ; Jin, Feng ; Jia, Zongqing ; Song, Weiguo ; Jin, Shanshan ; Cao, Weilong ; Liu, Binzhuo ; Li, Fahui ; Xu, Guangzhao ; Gao, Dingding

The development of novel inhibitors targeting urease that affects the colonization of Helicobacter pylori (H. pylori) is a promising strategy to address the growing challenge of antibiotic resistance. In this study, a novel urease covalent inhibitor, XBP2 (IC₅₀ = 0.14 ± 0.01 μM and MIC = 8 μg/mL), was identified through structure-based design using Ebselen as a template. XBP2 binds to a newly identified site, forming stable dipole interaction with residues ASP223 and HIS322, which enhances both stability and inhibitory activity against urease. It exhibits potent in vitro antibacterial activity, reducing cell apoptosis rates and significantly decreasing the fluorescence intensity of ROS and γH2AX in GES-1 cells infected with H. pylori. In the mouse gastritis model infected with H. pylori, XBP2 exhibits significant gastric mucosal protective effects. High-dose XBP2 (50 mg/kg) effectively prevented pathological changes such as bleeding and hyperplasia. Furthermore, acute toxicity test revealed that XBP2 does not display any detectable toxicity. These findings not only expand the structural diversity of Ebselen derivatives but also provide valuable insights for developing targeted therapies for eradicating H. pylori.

2024-05-01·European Journal of Medicinal Chemistry

Quantum chemistry calculation-aided discovery of potent small-molecule mimics of glutathione peroxidases for the treatment of cisplatin-induced hearing loss

Article

作者: Qiu, Siyu ; Zhang, Tianyi ; Ma, Xinyuan ; Lin, Hongyan ; Zheng, Zhiwei ; He, Yingzi ; Gao, Xing ; Zhao, Fengping ; Zhu, Kongkai ; Zheng, Canhui ; Wang, Wentao

Hearing loss (HL) is a health burden that seriously affects the quality of life of cancer patients receiving platinum-based chemotherapy, and few FDA-approved treatment specifically targets this condition. The main mechanisms that contribute to cisplatin-induced hearing loss are oxidative stress and subsequent cell death, including ferroptosis revealed by us as a new mechanism recently. In this study, we employed the frontier molecular orbital (FMO) theory approach as a convenient prediction method for the glutathione peroxidase (GPx)-like activity of isoselenazolones and discovered new isoselenazolones with great GPx-like activity. Notably, compound 19 exhibited significant protective effects against cisplatin-induced hair cell (HC) damage in vitro and in vivo and effectively reverses cisplatin-induced hearing loss through oral administration. Further investigations revealed that this compound effectively alleviated hair cell oxidative stress, apoptosis and ferroptosis. This research highlights the potential of GPx mimics as a therapeutic strategy against cisplatin-induced hearing loss. The application of quantum chemistry (QC) calculations in the study of GPx mimics sheds light on the development of new, innovative treatments for hearing loss.

2023-02-09·Journal of Medicinal Chemistry1区 · 医学

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

1区 · 医学

Article

作者: Giurg, Mirosław ; Mazzei, Luca ; Ciurli, Stefano ; Macegoniuk, Katarzyna ; Mucha, Artur ; Burda-Grabowska, Małgorzata ; Kaleta, Rafał ; Tabor, Wojciech ; Grabowiecka, Agnieszka ; Berlicki, Łukasz ; Cianci, Michele ; Olech, Kamila

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 K_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 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.

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