1,2-Benzisoselenazol-3(2H)-one Derivatives As a New Class of Bacterial Urease Inhibitors

Abstract

Urease inhibitors are considered promising compounds for the treatment of ureolytic bacterial infections, particularly infections resulting from Helicobacter pylori in the gastric tract. Herein, we present the synthesis and the inhibitory activity of novel and highly effective organoselenium compounds as inhibitors of Sporosarcina pasteurii and Helicobacter pylori ureases. These studied compounds represent a class of competitive reversible urease inhibitors. The most active compound, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen), displayed Ki values equal to 2.11 and 226 nM against S. pasteurii and H. pylori enzymes, respectively, indicating ebselen as one of the most potent low-molecular-weight inhibitors of bacterial ureases reported to date. Most of these molecules penetrated through the cell membrane of the Gram-negative bacteria Escherichia coli (pGEM::ureOP) in vitro. Furthermore, whole-cell studies on the H. pylori J99 reference strain confirmed the high efficiency of the examined organoselenium compounds as urease inhibitors against pathogenic bacteria.

Aminophosphinates against Helicobacter pylori ureolysis—Biochemical and whole-cell inhibition characteristics

“…The molecular modeling studies of compound 13 binding indicated that amino groups present in the inhibitor structure form hydrogen bonds with carbonyls of Ala170 and Ala366, while the phosphinic moiety interacts with both nickel(II) ions [27]. This type of binding in the bacterial urease active site makes the aminophosphinic class of inhibitors universal, contrary to structures designed to target the thiol group of cysteines, which in some pathogenic ureases are not present at locations that are relevant to enzyme activity [40, 41]. …”

Reaction of bis[(2-chlorocarbonyl)phenyl] Diselenide with Phenols, Aminophenols, and Other Amines towards Diphenyl Diselenides with Antimicrobial and Antiviral Properties

“…The tremendous efforts in this area has led to the identification of many bioactive structures [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Several enzymes, among them thioredoxin reductase [ 36 , 48 ], bacterial urease [ 49 ], and plasma membrane H+-ATPase [ 50 , 51 , 52 ], were suggested as targets for organoselenium compounds with antimicrobial properties. Furthermore, it has been reported that the antiviral effects of organoselenium compounds might be related to the inhibition of hepatitis C virus NS3 helicase [ 28 ], HIV-1 capsid dimerization [ 29 ], and nucleocapsid protein 7 [ 30 ].…”

Synthetic Approaches to Organoselenium Derivatives with Antimicrobial and Anti-Biofilm Activity

“…In the context of antimicrobial drug development, ebselen and its derivatives have been reported to: The plausible molecular mechanism behind the multiple activities of ebselen might derive from its ability to covalently Furthermore, ebselen has an inhibitory effect on H + /K + ATPase. This suggests a potential application in the treatment of H. pylori infection, as reported by Macegoniuk and co-workers [11]. Ebselen and its derivatives have also the ability to inhibit bacterial urease [11].…”

“…This suggests a potential application in the treatment of H. pylori infection, as reported by Macegoniuk and co-workers [11]. Ebselen and its derivatives have also the ability to inhibit bacterial urease [11].…”