scholarly journals Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1305
Author(s):  
Kaja Rožman ◽  
Evan M. Alexander ◽  
Eva Ogorevc ◽  
Krištof Bozovičar ◽  
Izidor Sosič ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
New Drugs ◽  
Irreversible Inhibitor ◽  
Inhibitory Potency ◽  
Reversible Inhibitors ◽  
Biochemical Assays ◽  
Fundamental Process ◽  
Psoralen Derivatives ◽  
Living Organisms ◽  
Derivatives Of

Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the Mycobacterium tuberculosis proteasome in low micromolar concentrations. The best inhibitors, i.e., 8, 11, 13 and 15, exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. N-(cyanomethyl)acetamide 8 (Ki = 5.6 µM) and carboxaldehyde-based derivative 15 (Ki = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters 11 and 13 irreversibly inhibited the enzyme with Ki values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, PR-957, is a noncompetitive irreversible inhibitor of the mycobacterial proteasome (Ki = 5.2 ± 1.9 µM, kinact/Ki = 96 ± 41 M−1·s−1). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis.

Identification of promising objects for the synthesis of thiosulphonate derivatives of benzoquinone and hydroquinone

2021 ◽  
Vol 4 (2) ◽  
pp. 47-53
Author(s):  
N. Y. Monka ◽  
◽  
N. E. Stadnytska ◽  
I. R. Buchkevych ◽  
K. O. Kaplia ◽  
...  
Keyword(s):  
Biological Activity ◽  
Biological Activities ◽  
Experimental Studies ◽  
New Drugs ◽  
Reduced Form ◽  
Free Form ◽  
Wide Range ◽  
On Line ◽  
Living Organisms ◽  
Derivatives Of

Benzoquinone and its reduced form hydroquinone belong to phenolic compounds and are found in living organisms in free form or in glycosides. They are active substances of some medicinal plants and have a pharmacological effect on the human body. Accordingly, their derivatives are important objects for chemical synthesis and development of new drugs. This article presents the findings of the structural design of substances with benzoquinone or hydroquinone fragment and sulfur-containing compound. By use of appropriate on-line programs a predictive screening of the biological activity and cytotoxicity of thiosulfonate derivatives of benzoquinone and hydroquinone has been conducted. It has been found that they have immense methodological potential to be synthesized by substances with a wide range of biological activities and a high value of probable activity, which substantiates the feasibility of conducting experimental studies on their biological activity, particularly anticancer.

scholarly journals Faster, surer prediction: Harnessing automated microscopy for drug discovery

2005 ◽  
Vol 27 (5) ◽  
pp. 25-28 ◽  
Author(s):  
Alan J. Monk
Keyword(s):  
Drug Discovery ◽  
Screening Tool ◽  
Functional Unit ◽  
Early Stage ◽  
New Drugs ◽  
Biochemical Assays ◽  
Automated Microscopy ◽  
Phases Of Development ◽  
Living Organisms

As many as 60% of investigational new drugs fail in the later preclinical and clinical phases of development because of unsatisfactory absorption, distribution, metabolism, excretion and/or toxicity (ADMET) characteristics. There is therefore a great need for tools that can help to predict the ADMET response earlier in drug development, before valuable resources are wasted on compounds destined ultimately to fail. ADMET characteristics are reliant on many co-ordinated events and feedback pathways in the intact organism and cannot readily be measured accurately in in vitro biochemical assays. The cell, however, as the smallest intact functional unit of living organisms, can provide a useful model in which to carry out predictive ADMET studies. This article looks at automated microscopy and imaging as a useful screening tool in early-stage drug discovery.

scholarly journals On the Diversification of the Translation Apparatus across Eukaryotes

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Greco Hernández ◽  
Christopher G. Proud ◽  
Thomas Preiss ◽  
Armen Parsyan
Keyword(s):  
Model Organisms ◽  
Ecological Niches ◽  
Translational Machinery ◽  
Functional Differences ◽  
Profound Knowledge ◽  
Genome Wide ◽  
Translation Apparatus ◽  
Fundamental Process ◽  
Organismal Complexity ◽  
Living Organisms

Diversity is one of the most remarkable features of living organisms. Current assessments of eukaryote biodiversity reaches 1.5 million species, but the true figure could be several times that number. Diversity is ingrained in all stages and echelons of life, namely, the occupancy of ecological niches, behavioral patterns, body plans and organismal complexity, as well as metabolic needs and genetics. In this review, we will discuss that diversity also exists in a key biochemical process, translation, across eukaryotes. Translation is a fundamental process for all forms of life, and the basic components and mechanisms of translation in eukaryotes have been largely established upon the study of traditional, so-called model organisms. By using modern genome-wide, high-throughput technologies, recent studies of many nonmodel eukaryotes have unveiled a surprising diversity in the configuration of the translation apparatus across eukaryotes, showing that this apparatus is far from being evolutionarily static. For some of the components of this machinery, functional differences between different species have also been found. The recent research reviewed in this article highlights the molecular and functional diversification the translational machinery has undergone during eukaryotic evolution. A better understanding of all aspects of organismal diversity is key to a more profound knowledge of life.

New hydrazides derivatives of isoniazid against Mycobacterium tuberculosis: Higher potency and lower hepatocytotoxicity

2018 ◽  
Vol 146 ◽  
pp. 529-540 ◽  
Author(s):  
Frederico Silva Castelo-Branco ◽  
Evanoel Crizanto de Lima ◽  
Jorge Luiz de Oliveira Domingos ◽  
Angelo C. Pinto ◽  
Maria Cristina S. Lourenço ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Derivatives Of

A new group of potential antituberculotics: N-(2-pyridylmethyl)salicylamides and N-(3-pyridylmethyl)salicylamides

2011 ◽  
Vol 65 (1) ◽  
Author(s):  
Eva Petrlíková ◽  
Karel Waisser ◽  
Karel Palát ◽  
Jiří Kuneš ◽  
Jarmila Kaustová
Keyword(s):  
Hydrogen Bond ◽  
Mycobacterium Tuberculosis ◽  
Quantitative Relationship ◽  
Antimycobacterial Activity ◽  
Carbonyl Groups ◽  
In Vitro Activity ◽  
Salicylamide Derivatives ◽  
Layer Chromatography ◽  
Derivatives Of

AbstractAs a part of our systematic study of antimycobacterially active derivatives of salicylamides, a series of nineteen derivatives of N-(2-pyridylmethyl)salicylamides and N-(3-pyridylmethyl)salicylamides was synthesised. The compounds exhibited in vitro activity against Mycobacterium tuberculosis and M. avium. Their lipophilicity, R M, was measured by thin layer chromatography on silica gel impregnated with trioctadecylsilane and the logarithm of the partition coefficient (octanol-water), logP, was calculated. Both the parameters of lipophilicity correlated. The quantitative relationship between the structure and antimycobacterial activity was calculated. Antimycobacterial activity increased with an increase in lipophilicity. The N-(2-pyridylmethyl)salicylamide derivatives were more active than the derivatives of isomeric N-(3-pyridylmethyl)salicylamides. The geometry of compounds was calculated and the calculation was verified by measuring the length of the hydrogen bond between hydroxyl and carbonyl groups on the salicylic moiety.

scholarly journals Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1259 ◽  
Author(s):  
José E. S. Nunes ◽  
Mario A. Duque ◽  
Talita F. de Freitas ◽  
Luiza Galina ◽  
Luis F. S. M. Timmers ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Rational Design ◽  
Shikimate Pathway ◽  
Chemotherapeutic Agents ◽  
New Drugs ◽  
Patient Treatment ◽  
Drug Resistant ◽  
Mycobacterium Tuberculosis Infection ◽  
Selective Toxicity ◽  
Prophylactic Measures

Roughly a third of the world’s population is estimated to have latent Mycobacterium tuberculosis infection, being at risk of developing active tuberculosis (TB) during their lifetime. Given the inefficacy of prophylactic measures and the increase of drug-resistant M. tuberculosis strains, there is a clear and urgent need for the development of new and more efficient chemotherapeutic agents, with selective toxicity, to be implemented on patient treatment. The component enzymes of the shikimate pathway, which is essential in mycobacteria and absent in humans, stand as attractive and potential targets for the development of new drugs to treat TB. This review gives an update on published work on the enzymes of the shikimate pathway and some insight on what can be potentially explored towards selective drug development.

scholarly journals A Study on Magnetic Removal of Hexavalent Chromium from Aqueous Solutions Using Magnetite/Zeolite-X Composite Particles as Adsorbing Material

2020 ◽  
Vol 21 (8) ◽  
pp. 2707 ◽  
Author(s):  
Maria-Elisavet Kouli ◽  
George Banis ◽  
Maria G. Savvidou ◽  
Angelo Ferraro ◽  
Evangelos Hristoforou
Keyword(s):  
Aqueous Solutions ◽  
Synthesis And Characterization ◽  
Composite Particles ◽  
Composite Nanomaterials ◽  
Zeolite X ◽  
Industrial Activities ◽  
Living Organisms ◽  
Derivatives Of ◽  
Toxic Ions

Toxic and heavy metals are considered harmful derivatives of industrial activities; they are not biodegradable and their accumulation in living organisms can become lethal. Among other heavy and toxic metals, chromium is considered hazardous, especially in the hexavalent (Cr6+) form. Numerous established studies show that exposure to Cr6+ via drinking water leads to elevated chromium levels in tissues, which may result in various forms of cancer. The purpose of this research is to synthesize magnetite/zeolite-X composite particles for the adsorption and magnetic removal of Cr6+ ions from aqueous solutions. Synthesis and characterization of such composite nanomaterials, along with an initial experimental evaluation of Cr6+ removal from water-based solution, are presented. Results show that zeolite-X is a very promising zeolite form, that when bound to magnetic nanoparticles can be used to trap and magnetically remove toxic ions from aqueous solutions.

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