Recent Efforts in the Discovery of Urease Inhibitor Identifications

2021 ◽  
Vol 21 ◽  
Author(s):  
Wan-Qin Song ◽  
Mei-Ling Liu ◽  
Su-Ya Li ◽  
Zhu-Ping Xiao
Keyword(s):  
Drug Target ◽  
Ureaplasma Urealyticum ◽  
Positive Control ◽  
Acetohydroxamic Acid ◽  
Past Century ◽  
Urease Inhibitors ◽  
Urease Inhibitor ◽  
The Past ◽  
Soil Urease ◽  
Ic50 Values

: Urease is an attractive drug target for designing anti-infective agents against pathogens such as Helicobacter pylori, Proteus mirabilis, and Ureaplasma urealyticum. In the past century, hundreds of medicinal chemists focused their efforts on explorations of urease inhibitors. Despite the FDA’s approval of acetohydroxamic acid as a urease inhibitor for the treatment of struvite nephrolithiasis and the widespread use of N-(n-butyl)thiophosphoric triamide as a soil urease inhibitor as nitrogen fertilizer synergists in agriculture, urease inhibitors with high potency and safety are urgently needed. Exploration of novel urease inhibitors has therefore become a hot research topic recently. Herein, inhibitors identified worldwide from 2016 to 2021 have been reviewed. They structurally belong to more than 20 classes of compounds such as urea/thioure analogues, hydroxamic acids, sulfonamides, metal complexes, and triazoles. Some inhibitors showed excellent potency with IC50 values lower than 10 nM, having 10000-fold higher potency than the positive control thiourea.

Synthesis and Structure−Activity Relationship Studies of N-monosubstituted Aroylthioureas as Urease Inhibitors

2020 ◽  
Vol 16 ◽  
Author(s):  
Wei-Wei Ni ◽  
Hai-Lian Fang ◽  
Ya-Xi Ye ◽  
Wei-Yi Li ◽  
Li Liu ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Mammalian Cells ◽  
Intact Cell ◽  
Linear Regression Analysis ◽  
Positive Control ◽  
Acetohydroxamic Acid ◽  
Urease Inhibitors ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Low Cytotoxicity

Background: Thiourea is a classical urease inhibitor usually as a positive control, and many N,N`-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N`-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thioureas with a tiny thiourea motif could theoretically bind into the active pocket as thiourea. Objective: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. Methods: Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated viasurface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics. Results: Compounds b2, b11and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in intact cell, with IC50 values being 90-to 450-fold and 5-to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed IC50 value of 0.060 ±0.004μM against cell-free urease, which bound to urea binding site with a very low KDvalue (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11was also demonstrated having very low cytotoxicity to mammalian cells. Conclusion: These results revealed that N-monosubstituted aroylthioureas clearly bind the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by ure-ase-containing pathogens.

Synthesis and Assessment of 3-Substituted Phenazines as Novel Antichlamydial Agents

2020 ◽  
Vol 16 (3) ◽  
pp. 413-421
Author(s):  
Xiaofeng Bao ◽  
Ziyi Liu ◽  
Min Ni ◽  
Chao Xia ◽  
Shunxin Xu ◽  
...  
Keyword(s):  
Suzuki Reaction ◽  
Coupling Reaction ◽  
Antibacterial Activities ◽  
Host Cells ◽  
Developmental Cycle ◽  
Past Century ◽  
The Past ◽  
Cross Coupling Reaction ◽  
Ic50 Values ◽  
Low Toxicity

Background: In the past century, many phenazines were isolated from the marine microorganism, and some of these phenazines possessed potent antibacterial activities. We found that a few of the synthesized 4-substituted phenazines could block the infectivity of chlamydiae without host cell toxicity. Objective: The aim of this study was to design and synthesize two series of novel 3-substituted phenazines to find novel antichlamydial agents. Methods: The 3-substituted phenazines were synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 3-bromo-1-methoxyphenazine. The antichlamydial activity of these synthesized compounds was evaluated by determining their effect on the yield of infectious progeny EBs. Cytotoxicity of these compounds on host cells was assessed by the treatment of uninfected HeLa cells using WST-1 method. Results: Most of the 3-substituted phenazines possessed potent antichlamydial activity with IC50 values from 0.15 to 12.08 μM against Chlamydia trachomatis L2, C. muridarum MoPn and C. pneumoniae AR39. Among them, 7d and 9a exhibited better antichlamydial activity with IC50 values from 0.20 to 1.01 μM while they have no apparent cytotoxicity to host cells. Biological assay disclosed that both 7d and 9a inhibited chlamydial infection by reducing elementary body infectivity and disturbing chlamydial growth during the whole chlamydial developmental cycle. Conclusion: Our findings suggested that 3-substituted phenazine derivatives might be a promising class of therapeutic agents for chlamydial infections. More effective phenazines with low toxicity could be acquired through further chemical modification on C-3 position rather than C-4 position of phenazine.

scholarly journals Chelerythrine Chloride: A Potential Rumen Microbial Urease Inhibitor Screened by Targeting UreG

2021 ◽  
Vol 22 (15) ◽  
pp. 8212
Author(s):  
Xiaoyin Zhang ◽  
Yue He ◽  
Zhanbo Xiong ◽  
Min Li ◽  
Ming Li ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Utilization Efficiency ◽  
Nitrogen Excretion ◽  
Inhibition Mechanism ◽  
Titration Calorimetry ◽  
Acetohydroxamic Acid ◽  
In Vitro Tests ◽  
Urease Inhibitors ◽  
Urease Inhibitor ◽  
Chelerythrine Chloride

Inhibition of ruminal microbial urease is of particular interest due to its crucial role in regulating urea-N utilization efficiency and nitrogen pollution in the livestock industry. Acetohydroxamic acid (AHA) is currently the only commercially available urease inhibitor, but it has adverse side effects. The urease accessory protein UreG, which facilitates the functional incorporation of the urease nickel metallocentre, has been proposed in developing urease inhibitor through disrupting urease maturation. The objective of this study was to screen natural compounds as potential urease inhibitors by targeting UreG in a predominant ruminal microbial urease. In silico screening and in vitro tests for potential inhibitors were performed using molecular docking and an assay for the GTPase activity of UreG. Chelerythrine chloride was selected as a potential urease inhibitor of UreG with an inhibition concentration IC50 value of 18.13 μM. It exhibited mixed inhibition, with the Ki value being 26.28 μM. We further explored its inhibition mechanism using isothermal titration calorimetry (ITC) and circular dichroism (CD) spectroscopy, and we found that chelerythrine chloride inhibited the binding of nickel to UreG and induced changes in the secondary structure, especially the α-helix and β-sheet of UreG. Chelerythrine chloride formed a pi-anion interaction with the Asp41 residue of UreG, which is an important residue in initiating the conformational changes of UreG. In conclusion, chelerythrine chloride exhibited a potential inhibitory effect on urease, which provided new evidence for strategies to develop novel urease inhibitors targeting UreG to reduce nitrogen excretion from ruminants.

The zoonotic potential of bat-borne coronaviruses

2020 ◽  
Vol 4 (4) ◽  
pp. 365-381
Author(s):  
Ny Anjara Fifi Ravelomanantsoa ◽  
Sarah Guth ◽  
Angelo Andrianiaina ◽  
Santino Andry ◽  
Anecia Gentles ◽  
...  
Keyword(s):  
Genetic Material ◽  
Field Research ◽  
Sympatric Species ◽  
Animal Origin ◽  
Mammalian Host ◽  
Past Century ◽  
The Past ◽  
Novel Host ◽  
Horseshoe Bat ◽  
Human Infections

Seven zoonoses — human infections of animal origin — have emerged from the Coronaviridae family in the past century, including three viruses responsible for significant human mortality (SARS-CoV, MERS-CoV, and SARS-CoV-2) in the past twenty years alone. These three viruses, in addition to two older CoV zoonoses (HCoV-229E and HCoV-NL63) are believed to be originally derived from wild bat reservoir species. We review the molecular biology of the bat-derived Alpha- and Betacoronavirus genera, highlighting features that contribute to their potential for cross-species emergence, including the use of well-conserved mammalian host cell machinery for cell entry and a unique capacity for adaptation to novel host environments after host switching. The adaptive capacity of coronaviruses largely results from their large genomes, which reduce the risk of deleterious mutational errors and facilitate range-expanding recombination events by offering heightened redundancy in essential genetic material. Large CoV genomes are made possible by the unique proofreading capacity encoded for their RNA-dependent polymerase. We find that bat-borne SARS-related coronaviruses in the subgenus Sarbecovirus, the source clade for SARS-CoV and SARS-CoV-2, present a particularly poignant pandemic threat, due to the extraordinary viral genetic diversity represented among several sympatric species of their horseshoe bat hosts. To date, Sarbecovirus surveillance has been almost entirely restricted to China. More vigorous field research efforts tracking the circulation of Sarbecoviruses specifically and Betacoronaviruses more generally is needed across a broader global range if we are to avoid future repeats of the COVID-19 pandemic.

PCSK9 inhibition for LDL lowering and beyond – implications for patients with peripheral artery disease

VASA ◽  
2018 ◽  
Vol 47 (3) ◽  
pp. 165-176 ◽  
Author(s):  
Katrin Gebauer ◽  
Holger Reinecke
Keyword(s):  
Cardiovascular Risk ◽  
Risk Reduction ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Past Century ◽  
Pcsk9 Inhibitors ◽  
Cardiovascular Risk Reduction ◽  
Simultaneous Application ◽  
The Past ◽  
Pcsk9 Inhibition

Abstract. Low-density lipoprotein cholesterol (LDL-C) has been proven to be a causal factor of atherosclerosis and, along with other triggers like inflammation, the most frequent reason for peripheral arterial disease. Moreover, a linear correlation between LDL-C concentration and cardiovascular outcome in high-risk patients could be established during the past century. After the development of statins, numerous randomized trials have shown the superiority for LDL-C reduction and hence the decrease in cardiovascular outcomes including mortality. Over the past decades it became evident that more intense LDL-C lowering, by either the use of highly potent statin supplements or by additional cholesterol absorption inhibitor application, accounted for an even more profound cardiovascular risk reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serin protease with effect on the LDL receptor cycle leading to its degradation and therefore preventing continuing LDL-C clearance from the blood, is the target of a newly developed monoclonal antibody facilitating astounding LDL-C reduction far below to what has been set as target level by recent ESC/EAS guidelines in management of dyslipidaemias. Large randomized outcome trials including subjects with PAD so far have been able to prove significant and even more intense cardiovascular risk reduction via further LDL-C debasement on top of high-intensity statin medication. Another approach for LDL-C reduction is a silencing interfering RNA muting the translation of PCSK9 intracellularly. Moreover, PCSK9 concentrations are elevated in cells involved in plaque composition, so the potency of intracellular PCSK9 inhibition and therefore prevention or reversal of plaques may provide this mechanism of action on PCSK9 with additional beneficial effects on cells involved in plaque formation. Thus, simultaneous application of statins and PCSK9 inhibitors promise to reduce cardiovascular event burden by both LDL-C reduction and pleiotropic effects of both agents.

Archaeology in the Past Century

1901 ◽  
Vol 51 (1309supp) ◽  
pp. 20976-20977
Author(s):  
W. M. Flinders Petrje
Keyword(s):  
Past Century ◽  
The Past

Catholicism and Cosmopolitanism: the Confluence of Three Catholic Scholars and the Cosmopolitan Democrats on State Sovereignty and the Future of Global Governance

2016 ◽  
Vol 3 (2) ◽  
pp. 37-51
Author(s):  
Matthew Bagot
Keyword(s):  
Global Governance ◽  
State Sovereignty ◽  
Current Debate ◽  
Past Century ◽  
Jacques Maritain ◽  
The Past ◽  
Technological Advances ◽  
The Future ◽  
Cosmopolitan Democracy ◽  
Catholic Tradition

One of the central questions in international relations today is how we should conceive of state sovereignty. The notion of sovereignty—’supreme authority within a territory’, as Daniel Philpott defines it—emerged after the Treaty of Westphalia in 1648 as a result of which the late medieval crisis of pluralism was settled. But recent changes in the international order, such as technological advances that have spurred globalization and the emerging norm of the Responsibility to Protect, have cast the notion of sovereignty into an unclear light. The purpose of this paper is to contribute to the current debate regarding sovereignty by exploring two schools of thought on the matter: first, three Catholic scholars from the past century—Luigi Sturzo, Jacques Maritain, and John Courtney Murray, S.J.—taken as representative of Catholic tradition; second, a number of contemporary political theorists of cosmopolitan democracy. The paper argues that there is a confluence between the Catholic thinkers and the cosmopolitan democrats regarding their understanding of state sovereignty and that, taken together, the two schools have much to contribute not only to our current understanding of sovereignty, but also to the future of global governance.

Aftershocks

2017 ◽  
Author(s):  
Seva Gunitsky
Keyword(s):  
Twentieth Century ◽  
Regime Change ◽  
International System ◽  
Political Legitimacy ◽  
Great Powers ◽  
Past Century ◽  
The Past ◽  
Sudden Rise ◽  
The World ◽  
National Borders

Over the past century, democracy spread around the world in turbulent bursts of change, sweeping across national borders in dramatic cascades of revolution and reform. This book offers a new global-oriented explanation for this wavelike spread and retreat—not only of democracy but also of its twentieth-century rivals, fascism, and communism. The book argues that waves of regime change are driven by the aftermath of cataclysmic disruptions to the international system. These hegemonic shocks, marked by the sudden rise and fall of great powers, have been essential and often-neglected drivers of domestic transformations. Though rare and fleeting, they not only repeatedly alter the global hierarchy of powerful states but also create unique and powerful opportunities for sweeping national reforms—by triggering military impositions, swiftly changing the incentives of domestic actors, or transforming the basis of political legitimacy itself. As a result, the evolution of modern regimes cannot be fully understood without examining the consequences of clashes between great powers, which repeatedly—and often unsuccessfully—sought to cajole, inspire, and intimidate other states into joining their camps.

Variable oil and argumentative conflict in the Middle East

2020 ◽  
pp. 824
Author(s):  
Malik Daham Mata’ab
Keyword(s):  
Middle East ◽  
Past Century ◽  
Large Area ◽  
The Past ◽  
The World

Oil has formed since its discovery so far one of the main causes of global conflict, has occupied this energy map a large area of conflict the world over the past century, and certainly this matter will continue for the next period in our century..

Mahmood Hasan Khan. Underdevelopment and Agrarian Structure in Pakistan. Boulder, Colorado: Westview Press. 1981. pp.xviii+ 307.

1981 ◽  
Vol 20 (4) ◽  
pp. 465-468 ◽  
Author(s):  
Douglas H. Perry
Keyword(s):  
Ownership Structure ◽  
Land Reform ◽  
Land Ownership ◽  
Past Century ◽  
The Past ◽  
Ownership Patterns ◽  
Agrarian Structure

Students of the land ownership patterns in Pakistan have always been hampered by extreme lack of data, neither the 1960 census nor the 1972 census reveal anything about the actual ownership structure of land. Khan's book goes some distance in providing numbers on land ownership (for 1971 and 1976), and also documents methods and failures of land reform efforts over the past century in Pakistan, disaggregated to show efforts in this regard in both the provinces of Sind and Punjab. The book actually provides an overwhelming amount of data - some 87 pages of charts and tables document a book of under 200 pages of text.

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