Pylori Urease Inhibitors Research Articles

An efficient biosensor based on the synergistic catalysis of Helicobacter pylori urease b subunit and nanoplatinum for urease inhibitors screening and antagonistic mechanism analyzing

Helicobacter pylori (H. pylori) is the main non-genetic factor leading to gastric cancer. Due to the important role of urease produced by H. pylori in its initial colonization, survival, and infection, the activity inhibition of urease has been proven to be a promising therapeutic strategy for H. pylori infection. Therefore, the screening of effective urease inhibitors has become an important direction for the development of new therapeutic drugs. In this study, a novel biosensor for rapid screening of H. pylori urease inhibitors was constructed based on glassy carbon electrode (GCE) modified by heterologously expressed H. pylori 26695 urease b subunit (HPUb), Pt nanoparticles, and nanoporous gold (NPG). Five inhibitors were successfully screened for HPUb using the proposed biosensor (HPUb/Pt/NPG/GCE). The inhibition constants calculated according to the established mathematical model indicated that the inhibitory intensity order of these inhibitors was methylurea > acetamide > formamide > acetohydroxamic acid > hydroxyurea. Combining the inhibition constant of urease inhibitors with the molecular binding mechanism of the urease inhibitor and HPUb, it can be inferred that the non-polar long-chain modification of one of the primary amino groups based on the molecular structure of urea is a promising direction for the development of high-efficiency urease inhibitors. The elucidation of this mechanism will provide a theoretical foundation and new ideas for the design of competitive urease inhibitors based on urea structure and the development of new anti H. pylori drugs.

Zerumbone Inhibits Helicobacter pylori Urease Activity.

Helicobacter pylori (H. pylori) produces urease in order to improve its settlement and growth in the human gastric epithelium. Urease inhibitors likely represent potentially powerful therapeutics for treating H. pylori; however, their instability and toxicity have proven problematic in human clinical trials. In this study, we investigate the ability of a natural compound extracted from Zingiber zerumbet Smith, zerumbone, to inhibit the urease activity of H. pylori by formation of urease dimers, trimers, or tetramers. As an oxygen atom possesses stronger electronegativity than the first carbon atom bonded to it, in the zerumbone structure, the neighboring second carbon atom shows a relatively negative charge (δ−) and the next carbon atom shows a positive charge (δ+), sequentially. Due to this electrical gradient, it is possible that H. pylori urease with its negative charges (such as thiol radicals) might bind to the β-position carbon of zerumbone. Our results show that zerumbone dimerized, trimerized, or tetramerized with both H. pylori urease A and urease B molecules, and that this formation of complex inhibited H. pylori urease activity. Although zerumbone did not affect either gene transcription or the protein expression of urease A and urease B, our study demonstrated that zerumbone could effectively dimerize with both urease molecules and caused significant functional inhibition of urease activity. In short, our findings suggest that zerumbone may be an effective H. pylori urease inhibitor that may be suitable for therapeutic use in humans.

Development of Schiff bases from Amikacin: Synthesis, Antibacterial, Anti-urease Activities and Molecular Docking Studies

Background:The use of antibiotics has compromised due to the appearance of multidrug- resistant strains and decreased susceptibility of strains to antibiotics. Antibiotic resistance has become a worldwide threat as well as Helicobacter pylori induced gastric cancer is a major problem nowadays. Therefore, it is the need of time to synthesize potent anti-urease motifs.Introduction:Schiff bases represent a large class of biologically active compounds that exhibited a broad spectrum of biological activities. Amikacin is an important drug used against multidrugresistant species of microbes. Therefore, imine derivatives of amikacin may help to reduce the resistance of microbes and to treat the Helicobacter pylori induced stomach problems by inhibiting the Helicobacter Pylori Urease enzyme.Methods:Schiff bases of amikacin were synthesized and screened for in-vitro antibacterial assay performed by well diffusion method against Bacillus megaterium (Bm), Bacillus subtilis (Bs), Stenotrophomonas maltophilia (Sm), Staphylococcus aureus (Sa), Micrococcus luteus (Ml), Serratia marcescens (S. mar), Escherichia coli (E. coli) and anti-urease activity was performed by Indophenol method. Structures confirmed by IR, 1HNMR and 13CNMR spectroscopy.Results:Compounds showed varying degrees of antibacterial effects. Schiff bases A2 and A8 exhibited potent urease inhibition activity with Ki values 0.2754 and 0.2908 μM, respectively and their binding affinity was calculated as greater than the standard drug.Conclusion:Derivatives of amikacin with aromatic rings were more active antibacterials than those with an aliphatic side chain. The potent anti-urease activity has been recorded for compounds A2 and A8. Therefore, they may serve as lead compounds in the discovery of Helicobacter pylori Urease inhibitors.

Identification of novel urease inhibitors: pharmacophore modeling, virtual screening and molecular docking studies

Pharmacophore modeling and atom-based three-dimensional quantitative structure–activity relationship (3D-QSAR) have been developed on N-acylglycino- and hippurohydroxamic acid derivatives, which are known potential inhibitors of urease. This is followed by virtual screening and ADMET (absorption, distribution, metabolism, excretion and toxicity) studies on a large library of known drugs in order to get lead molecules as Helicobacter pylori urease inhibitors. A suitable three-featured pharmacophore model comprising one H-bond acceptor and two H-bond donor features (ADD.10) has been found to be the best QSAR model. An external library of compounds (∼3000 molecules), pre-filtered using Lipinski’s rule of five, has been further screened using the pharmacophore model ADD.10. By analyzing the fitness of the hits with respect to the pharmacophore model and their binding interaction inside the urease active site, four molecules have been predicted to be extremely good urease inhibitors. Two of these have significant potential and should be taken up for further drug-designing process.

In vitro Assessment of Helicobacter pylori Ureases Inhibition by Honey Fractions

Pathogenic effects associated with Helicobacter pylori infection include peptic ulcer. Pathogenicity is mediated by the bacteria ureases. The emerging resistance of H. pylori to clarithromycin used in combination with amoxicillin in the treatment of H. pylori infection has necessitated the search for other means of combating the scourge of H. pylori, hence the search for potent H. pylori urease inhibitor. The aim of the study was to evaluate honey fractions obtained from different geographic zones for H. pylori urease inhibitory potentials. Chloroform and diethyl-ether were used to extract honey fractions (HS) and Manuka honey (HM). H. pylori ureases were obtained from a 48-h culture through sonication. Urease activity was measured spectrophotometrically by assaying the reduction in NADH in coupled urease-glutamate dehydrogenase (GDH) system, whereas urease inhibition was calculated by comparing the NADH oxidation rate before and after incubation with honey fractions. Urease inhibition by the HS and HM were time and concentration independent. Chloroform extract of HS showed 48 and 42% inhibitory activities against urease from H. pylori (369C) and H. pylori (ATCC 43526), respectively, wheeras diethyl ether extract of HM showed 45 and 51% inhibitory activities against urease from H. pylori (369C) and H. pylori (ATCC 43526), respectively. Dixon plot revealed that HM extract showed mixed inhibition pattern in a reversible inhibition kinetics. Honey fractions were good inhibitors of H. pylori urease and may serve as a template in the development of urease inhibitors in pharmaceuticals.

Synthesis, structure, and activity evaluation of two silver(I) complexes as Helicobacter pylori urease inhibitors

Two silver(I) compounds, [Ag(R,R-hxn)](C7H4BrO2) · 2H2O (I) (Chxn = 1,2-diaminocyclohexane) and [Ag(C5H6N2)2]2(C8H4O4) · 10H2O (II), were synthesized and complex I was structurally characterized by X-ray crystallography. Compound I contains a catena-(trans-1,2-diaminocyclohexane) silver polycation ([Ag(Chxn)]∞) in a roughly linear fashion, while II possesses a linear-type silver monocation. Compounds I and II were evaluated for their inhibitory activities against Helicobacter pylori urease in vitro. Both were found to have strong inhibitory activities against H. pylori urease comparable to that of acetohydroxamic acid.

Synthesis, molecular docking, and activity of Schiff-base copper(II) complex with N-n-butylsalicylaldiminate as Helicobacter pylori urease inhibitor

A Schiff-base copper(II) complex, bis(N-n-butylsalicylaldiminato)copper(II), was synthesized and its solid-state structure was determined by X-ray crystallography. Its inhibitory activity against Helicobacter pylori urease was evaluated in vitro and it showed strong inhibitory activity against urease (IC50 = 0.95 µM), compared with acetohydroxamic acid (IC50 = 42.47 µM) as a positive reference. A docking analysis using the AUTODOCK 4.0 program was performed to explain the potent inhibitory activity of the complex against urease.