scholarly journals Synthesis and multifaceted pharmacological activity of novel quinazoline NHE-1 inhibitors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexander Spasov ◽  
Alexander Ozerov ◽  
Pavel Vassiliev ◽  
Vadim Kosolapov ◽  
Natalia Gurova ◽  
...  
Keyword(s):  
Drug Target ◽  
Antidepressant Activity ◽  
Side Chain ◽  
Neural Network Modeling ◽  
Lead Compounds ◽  
Glycated Proteins ◽  
Starting Point ◽  
Inflammatory Activation ◽  
Nanomolar Range

AbstractThe Na+/H+ exchanger isoform 1 (NHE-1) attracts ongoing attention as a validated drug target for the management of cardiovascular and ocular diseases owing to cytoprotective, anti-ischemic and anti-inflammatory properties of NHE-1 inhibitors. Herein we report novel NHE-1 inhibitors realized via functionalization of N1-alkyl quinazoline-2,4(1H,3H)-dione and quinazoline-4(3H)-one with N-acylguanidine or 3-acyl(5-amino-1,2,4-triazole) side chain. Lead compounds show activity in a nanomolar range. Their pharmacophoric features were elucidated with neural network modeling. Several compounds combine NHE-1 inhibition with antiplatelet activity. Compound 6b reduces intraocular pressure in rats and effectively inhibits the formation of glycated proteins. Compounds 3e and 3i inhibit pro-inflammatory activation of murine macrophages, LPS-induced interleukin-6 secretion and also exhibit antidepressant activity similar to amiloride. Hence, novel compounds represent an interesting starting point for the development of agents against cardiovascular diseases, thrombotic events, excessive inflammation, long-term diabetic complications and glaucoma.

scholarly journals Synthesis And Multifaceted Pharmacological Activity of Novel Quinazoline NHE-1 Inhibitors

2021 ◽  
Author(s):  
Alexander Spasov ◽  
Alexander Ozerov ◽  
Pavel Vassiliev ◽  
Vadim Kosolapov ◽  
Natalia Gurova ◽  
...  
Keyword(s):  
Drug Target ◽  
Antidepressant Activity ◽  
Side Chain ◽  
Neural Network Modeling ◽  
Lead Compounds ◽  
Glycated Proteins ◽  
Starting Point ◽  
Inflammatory Activation ◽  
Nanomolar Range

Abstract The Na+/H+ exchanger isoform 1 (NHE-1) attracts ongoing attention as a validated drug target for the management of cardiovascular and ocular diseases owing to cytoprotective, anti-ischemic and anti-inflammatory properties of NHE-1 inhibitors. Herein we report novel NHE-1 inhibitors realized via functionalization of N1-alkyl quinazoline-2,4(1H,3H)-dione and quinazoline-4(3H)-one with N-acylguanidine or 3-acyl(5-amino-1,2,4-triazole) side chain. Lead compounds show activity in a nanomolar range. Their pharmacophoric features were elucidated with neural network modeling. Several compounds combine NHE-1 inhibition with antiplatelet activity. Compound 6b reduces intraocular pressure in rats and effectively inhibits the formation of glycated proteins. Compounds 3e and 3i inhibit pro-inflammatory activation of murine macrophages, LPS-induced interleukin-6 secretion and also exhibit antidepressant activity similar to amiloride. Hence, novel compounds represent an interesting starting point for the development of agents against cardiovascular diseases, thrombotic events, excessive inflammation, long-term diabetic complications and glaucoma.

Research for a sustainable European sugar sector

2010 ◽  
pp. 487-495
Author(s):  
Martin Bruhns ◽  
Peter Glaviè ◽  
Arne Sloth Jensen ◽  
Michael Narodoslawsky ◽  
Giorgio Pezzi ◽  
...  
Keyword(s):  
Sugar Industry ◽  
Research Priorities ◽  
Decision Makers ◽  
Sustainable Chemistry ◽  
Technology Platforms ◽  
Research Themes ◽  
Starting Point ◽  
Manufacturing Applications ◽  
European Technology

The paper is based on the results of international project entitled “Towards Sustainable Sugar Industry in Europe (TOSSIE)”. 33 research topics of major importance to the sugar sector are listed and briefly described, and compared with research priorities of the European Technology Platforms: “Food for Life”, “Sustainable Chemistry”, “Biofuels”, and “Plant for the Future”. Most topics are compatible with the research themes included in the COOPERATION part of the 7th Framework Program of the EU (2007-2013). However, some topics may require long-term R&D with the time horizon of up to 15 years. The list of topics is divided into four parts: Sugar manufacturing, Applications of biotechnology and biorefinery processing, Sugarbeet breeding and growing, Horizontal issues. Apart from possible use of the list by policy- and decision makers with an interest in sugarbeet sector, the description of each research topic can be used as a starting point in setting up a research project or other R&D activities.

scholarly journals Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

2021 ◽  
Vol 22 (13) ◽  
pp. 7236
Author(s):  
Endah Dwi Hartuti ◽  
Takaya Sakura ◽  
Mohammed S. O. Tagod ◽  
Eri Yoshida ◽  
Xinying Wang ◽  
...  
Keyword(s):  
Drug Target ◽  
De Novo ◽  
Dihydroorotate Dehydrogenase ◽  
Chemical Library ◽  
New Class ◽  
De Novo Biosynthesis ◽  
Starting Point ◽  
Novel Drugs ◽  
Low Toxicity ◽  
Fourth Step

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.

scholarly journals The Implications of the COVID-19 Pandemic on Religious Exercise: Preliminary Remarks

Laws ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 44
Author(s):  
Adelaide Madera
Keyword(s):  
Global Health ◽  
Health And Safety ◽  
Fundamental Rights ◽  
Special Issue ◽  
Health Crisis ◽  
Personal Lives ◽  
Regulatory Frameworks ◽  
Starting Point ◽  
Legal Contexts

Since 2020, the spread of COVID-19 has had an overwhelming impact not only on our personal lives, but also on domestic regulatory frameworks. Influential academics have strongly underlined that, in times of deep crisis, such as the current global health crisis, the long-term workability of legal systems is put to a severe test. In this period, in fact, the protection of health has been given priority, as a precondition that is orientating many current legal choices. Such an unprecedented health emergency has also raised a serious challenge in terms of fundamental rights and liberties. Several basic rights that normally enjoy robust protection under constitutional, supranational, and international guarantees, have experienced a devastating “suspension” for the sake of public health and safety, thus giving rise to a vigorous debate concerning whether and to what extent the pandemic emergency justifies limitations on fundamental rights. The present paper introduces the Special Issue on “The crisis of the religious freedom during the age of COVID-19 pandemic”. Taking as a starting point the valuable contributions of the participants in the Special Issue, it explores analogous and distinctive implications of the COVID-19 pandemic in different legal contexts and underlines the relevance of cooperation between religious and public actors to face a global health crisis.

scholarly journals Structural Basis for Inhibition of Protein-tyrosine Phosphatase 1B by Isothiazolidinone Heterocyclic Phosphonate Mimetics

2006 ◽  
Vol 281 (43) ◽  
pp. 32784-32795 ◽  
Author(s):  
Paul J. Ala ◽  
Lucie Gonneville ◽  
Milton C. Hillman ◽  
Mary Becker-Pasha ◽  
Min Wei ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Structural Basis ◽  
Side Chain ◽  
Protein Tyrosine Phosphatase 1B ◽  
Phosphate Binding ◽  
Protein Tyrosine ◽  
Starting Point ◽  
Network Of Hydrogen Bonds ◽  
Orthogonal Orientation

Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe182 of the flap, and the side chain of Arg221. When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors.

The significance of the Cα substituent in the selective inhibition of matrix metalloproteinases 1 and 9

2011 ◽  
Vol 392 (11) ◽  
Author(s):  
Riyad Domingo ◽  
Kelly Chibale ◽  
Edward D. Sturrock
Keyword(s):  
Hydrogen Bonding ◽  
Matrix Metalloproteinases ◽  
Active Sites ◽  
Unsaturated Compound ◽  
Selective Inhibition ◽  
Acid Group ◽  
Side Chain ◽  
Carboxylic Acid Group ◽  
Lead Compounds ◽  
Hydrogen Bonding Interactions

Abstract Matrix metalloproteinases (MMPs) cleave and degrade most components of the extracellular matrix, and unregulated MMP activity has been correlated to cancer and metastasis. Hence there is a burgeoning need to develop inhibitors that bind selectively to structurally similar MMPs. The inhibition profiles of peptidomimetics containing Cα substituents at the α,β unsaturated carbon were evaluated against the recombinant forms of ADAM17, MMP1, and MMP9. The dicarboxylic acid D2 and hydroxamate C2 inhibited MMP9 but not MMP1. The unsaturated compound E2 displayed selective inhibition for MMP1, compared with the saturated precursor C2, with an IC50 value of 3.91 μm. The molecular basis for this selectivity was further investigated by the molecular docking of E2 and D2 into the active sites of MMP1 and MMP9. These data demonstrate hydrogen-bonding interactions between the carbonyl group of the Cα substituent of E2 and the side chain of Asn180 present in the active site of MMP1. Conversely, the docked MMP9-D2 structure shows hydrophobic and hydrogen bonding between the ligand’s morpholine substituent and second carboxylic acid group with Leu187 and an amide, respectively. This study suggests that substituents other than P1′ and P2′ may confer selectivity among MMPs and may aid in the search for novel lead compounds.

Long-Term Forecasting and Optimization of Non-Stationary Well Operation Modes Through Neural Networks Simulation

2021 ◽  
Author(s):  
Roman Yurievich Ponomarev ◽  
Vladimir Evgenievich Vershinin
Keyword(s):  
Neural Network ◽  
Forecast Error ◽  
Optimal Solution ◽  
Hydrodynamic Modeling ◽  
Neural Network Modeling ◽  
Sharp Change ◽  
Technological Parameters ◽  
Production Wells ◽  
Long Term Forecasting

Abstract The article discusses the results of long-term forecasting of non-stationary technological modes of production wells using neural network modeling methods. The main difficulty in predicting unsteady modes is to reproduce the response of producing wells to a sharp change in the mode of one of the wells. Such jumps, as a rule, lead to a rapid increase in the forecast error. Training and forecasting of modes was carried out on the data of numerical hydrodynamic modeling. Two fields with significantly different properties, the number of wells and their modes of operation were selected as objects of modeling. Non-stationarity was set by changing the regime on one or several production wells at different points in time. The LSTM recurrent neural network carried out forecasting of production technological parameters. This made it possible to take into account the time-lagging influence of the wells on each other. It is shown that the LSTM neural network allows predicting unsteady technological modes of well operation with an accuracy of up to 5% for a period of 10 years. The solution of the problem of optimization of oil production is considered on the example of one of the models. It is shown that the optimal solution found by the neural network differs from the solution found by hydrodynamic modeling by 5%. At the same time, a significant gain in calculation time was achieved.

17α-HYDROXYLASE DEFICIENCY. A COMBINATION OF HYDROXYLATION DEFECT AND REVERSIBLE BLOCKADE IN ALDOSTERONE BIOSYNTHESIS

1979 ◽  
Vol 90 (3) ◽  
pp. 490-504 ◽  
Author(s):  
D. R. Rovner ◽  
J. W. Conn ◽  
E. L. Cohen ◽  
F. G. Berlinger ◽  
D. C. Kern ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Extracellular Fluid ◽  
Plasma Renin ◽  
Hydroxyl Group ◽  
Side Chain ◽  
Hydroxylase Deficiency ◽  
Resultant Increase

ABSTRACT We have studied the hormonal secretion and excretion patterns in a patient with the XX type of 17α-hydroxylase deficiency. In the untreated state, the patient's urine contained only those steroids which do not require 17-hydroxylation in their biosynthesis. Aldosterone was not produced in the patient and the metabolic product of its immediate precursor, 18-hydroxy-11-dehydro-tetrahydrocorticosterone, was excreted in markedly elevated amounts. This apparent complete block in 18 oxidation was reversible upon long-term ACTH suppression within 27 days. Direct in vitro incubation of the patient's adrenal gland removed at operation demonstrated, 1) the complete lack of 17α-hydroxylase activity, 2) the functional block in the ability to oxidize the hydroxyl group at the 18 methyl side chain. The addition of physiological concentrations of angiotensin to the incubation medium further showed, 3) angiotensin mildly stimulated the entire aldosterone biosynthetic pathway, 4) angiotensin directly stimulated the conversion of 18-hydroxycorticosterone to aldosterone. We propose that in this patient, 17-hydroxylase deficiency produced a decreased plasma concentration of cortisol, followed by stimulation of deoxycorticosterone production by ACTH. The resultant increase in extracellular fluid volume suppressed plasma renin activity. This resulted in a low plasma concentration of angiotensin II which directly suppressed oxidation of 18-hydroxycorticosterone to aldosterone. This defect has been called corticosterone methyl oxidase defect type 2.

scholarly journals Decision making in reverse logistics using system dynamics

2004 ◽  
Vol 14 (2) ◽  
pp. 259-272 ◽  
Author(s):  
P. Georgiadis ◽  
D. Vlachos
Keyword(s):  
Decision Making ◽  
System Dynamics ◽  
Reverse Logistics ◽  
Closed Loop ◽  
System Modeling ◽  
New Approach ◽  
Helpful Tool ◽  
Starting Point ◽  
Decision Making Tool

Reverse logistics is a modern field of consideration, research and study, providing helpful information on the operation of the closed-loop supply chain. Although the starting point of this field is traced back to the early 90?s, no standard method has been suggested, neither prevailed. The purpose of this paper is to introduce a new approach on the study of reverse logistics. It is actually a review on how System Dynamics (SD) can be a helpful tool when it is used in the reverse logistics field. The paper explains the basic theory of the system modeling and next it utilizes the reverse logistics model. Finally, an illustrative example shows how SD modeling can be used to produce a powerful long-term decision-making tool.

scholarly journals FDI in the Post-Soviet Space Three Decades after the Disintegration of the Soviet Union

2021 ◽  
Vol 14 (5) ◽  
pp. 30-60
Author(s):  
K. Kalotay ◽  
A. Sulstarova
Keyword(s):  
Soviet Union ◽  
Transition Economies ◽  
Structural Characteristics ◽  
Academic Research ◽  
Data Availability ◽  
Outward Fdi ◽  
Starting Point ◽  
Soviet Space ◽  
Post Soviet Space

The former Soviet Union disintegrated three decades ago. That momentous 1991 was not only the starting point for independence of the countries of the post-Soviet space but also the starting point for their transformation from centrally planned economy to capitalism, often with local specificities. At the moment of writing this article aiming at analysing the long-term, structural characteristics of inward and outward foreign direct investment (FDI), these 12 economies are facing new COVID-19-related challenges, different from the problems of transformation undertaken in the past decades. After a brief literature survey, in which the main issues raised by academic research are highlighted, the article analyses the long-term trends and the main characteristics (geographical and sectoral) of FDI, with special reference to greenfield project announcements from 2003 on (the starting year of data availability). It also explores how much economic development was based on either attracting inward or promoting outward FDI or both. The performance of the 12 post-Soviet economies is controlled against the performance of other transition economies such as the Baltic States, South-East Europe and/or the Visegrad Group. The article concludes that indeed efforts towards using inward or outward FDI for development has been modest, even if in inflows one can observe some convergence with the other transition economies, which have been relying more wittingly using FDI for their development.

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