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Super bacterial infection caused by metallo‐β‐lactamases (MβLs) has posed a serious public health threat, while developing inhibitors of MβLs is an ideal strategy to combat drug‐resistance. Here, seventeen sulfonylureas were synthesized and confirmed. Biological assay shown that these molecules effectively inhibited MβL ImiS, with an IC50 value in the range of 29.5–188.2 μM, and the best inhibitor competitively and irreversibly inhibited ImiS with a Ki value of 15.2 μM. Structure‐activity relationship analysis revealed that the chlorine‐substituted phenyl significantly raised inhibitory activity of sulfonylureas on ImiS. Antibacterial and chessboard dilution assays shown that the most sulfonylureas tested enhanced antimicrobial effect of meropenem (MER) on E. coli‐ImiS, and the two inhibitors with best effect resulted in an 8‐fold reduction in MIC of MER. Mice tests shown that the best inhibitor synergizing MER virtually diminished the load of E. coli‐ImiS in spleen and liver. Docking study revealed that the sulfonylurea reacts with ImiS mainly through the sulfonyl group, in which one of oxygen atoms coordinates to Zn(II), and forms two hydrogen bonds with Lys224 (2.1 Å) and His263 (3.1 Å). This work revealed the sulfonylureas are promising candidates for the development of ImiS inhibitors. [ABSTRACT FROM AUTHOR]

The main protease (Mpro) of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) represents a promising target for antiviral drugs aimed at combating COVID-19. Consequently, the development of Mpro inhibitor  is an ideal strategy for combating the virus. In this study, we identified twenty-two dithiocarbamates (1a-h), dithiocarbamate-Cu(II) complexes (2a-hCu) and disulfide derivatives (2a-e, 2i) as potent inhibitors of Mpro, with IC50 value range of 0.09-0.72, 0.9-24.7 and 15.1-111 µM, respectively, through FRET screening. The enzyme kinetics, inhibition mode, jump dilution, and DTT assay revealed that 1g may be a partial reversible inhibitor, while 2d and 2f-Cu are the irreversible and dose- and time-dependent inhibitors, potentially covalently binding to the target. Binding of 2d, 2f-Cu and 1g to Mpro was found to decrease the stability of the protein. Additionally, DTT assays and thermal shift assays indicated that 2f-Cu and 2d are the nonspecific and promiscuous cysteine protease inhibitor. ICP-MS implied that the inhibitory activity of 2f-Cu may stem from the uptake of Cu(II) by the enzyme. Cytotoxicity assays demonstrated that 2d and 1g exhibit low cytotoxicity, whereas 2f-Cu show certain cytotoxicity in L929 cells. Overall, this work presents two promising scaffolds for the development of Mpro inhibitors to combat COVID-19., (© 2024 Wiley‐VCH GmbH.)

A simple protocol for the noble-metal-free oxidative cyclization of enamines and t BuONO has been developed. This KI-mediated formal [4 + 1] cycloamination reaction provides a practical strategy for the synthesis of imidazole-4-carboxylic derivatives using t BuONO both as an aminating reagent and oxidant. The reaction features wide substrate scope and good functional tolerance for enamine compounds, even the unactivated ones.

Objective: To study the necessity, feasibility, security of carotid angioplasty and stenting (CAS) for symptomatic carotid stenosis combined with kinking., Methods: Twelve patients with symptomatic carotid stenosis and kinking demonstrated by digital subtraction angiography (DSA) received CAS from December 2003 to December 2009. There were 9 male and 3 female patients, age ranged from 59 to 77 years (mean 69.3 years). All the patients' clinical, imaging, intervention and follow up data were collected and analyzed., Results: All CAS procedures were successfully performed with 14 self-expandable stents placed. The mean degree of stenosis was reduced from 85.6% before stenting to 11.2% after stenting, the angle of kinking, according to Metz' category, were improved from less than 90° to more than 120° in each case. No perioperative procedure related stroke and transient ischemic attack (TIA) occurred. The clinical symptoms and signs of cerebral ischemia were improved or disappeared for all patients. During follow-up of these 12 patients for 6 to 72 months, one patient experienced ipsilateral carotid territory TIA and another patient experienced contralateral carotid territory TIA. DSA follow up of 5 patients demonstrated 1 case with in-stent restenosis and arterial kinking remote to the stent of internal carotid artery. CAS were performed again and CT angiography follow up demonstrated no kinking and restenosis 2 years after the intervention. Duplex scan of the other 7 patients demonstrated neither kinking nor restenosis., Conclusions: CAS seems to be feasible and safe for the patients with symptomatic kinking and stenosis, and maybe helpful to lower the risk of cerebral ischemia, but further study is needed.

Objectives: To investigate adverse factors that may hinder successful placement and stabilization of the microcatheter during endovascular therapy of micro-intracranial aneurysms (≤ 3 mm in maximum diameter), and to explore the relevant managements., Methods: Forty-six patients with fifty-one micro-intracranial aneurysms treated by endovascular therapy from June 2001 to October 2009 were retrospectively analyzed for their intervention data., Results: Adverse factors of optimal micro-catheterization mainly included, tortuosity of the proximal vessels (PVs) and the parent artery (PA), relative large gap in diameter among the PVs, the PA and the microcatheter, relative large divergence in direction among the PVs, the PA and the aneurysm dome, and stent deployed in the PA., Conclusions: Carefully considering the direction of the PVs and the PA, the aneurysm's location and dome orientation, choosing the microcatheter and microwire after balancing among their physical properties, as well as utilizing balloon and/or stent assistance, can facilitate micro-catheterization during endovascular treatment of micro-intracranial aneurysms.

Objective: To evaluate the feasibility and safety of endovascular treatment of ruptured and unruptured intracranial very small aneurysms (< or = 3 mm in maximal diameter)., Methods: Forty-eight intracranial very small aneurysms in 44 patients treated with endovascular therapy from June 2001 to August 2009 were reviewed retrospectively in clinical, imaging, interventional and follow-up data. Among 44 patients, there were 20 males and 24 females with a mean age of 57.8 years old. The Hunt-Kosnik grade was as follows: Grade 0 (n = 11); Grades I & II (n = 23); Grades III & IV (n = 9); and ungraded (n = 1). The sizes of 48 aneurysms were not more than 3 mm in maximal diameter. The locations of aneurysms were as follows: ACoA (n = 11), MCA (n = 8), PCoA (n = 14), ICA (n = 12), pericallosal artery (n = 1), VA (n = 1) and PICA (n = 1). Thirty-nine aneurysms were embolized with coil, of which 13 with stent assistance and 6 by balloon remodeling technique. The other 9 aneurysms underwent sole stent placement in parent artery., Results: Among 39 coiling aneurysms, 100% occlusion was achieved in 9 aneurysms, 90% in 20, 80% in 9 and less than 80% in 1 respectively. Only one aneurysm ruptured during coiling. Two patients had transient hemiparesis and one patient had ataxia caused by bilateral cerebellar infarction postoperatively. All patients were clinically followed up for 4-90 months and no recurrent hemorrhage occurred. Thirteen patients received repeat angiography at 4-72 months post-treatment. And no radiological re-growth was detected., Conclusion: Endovascular treatment of ruptured and unruptured intracranial very small aneurysms seems to be technically feasible, relatively safe and practically effective.