Molecules

Open AccessEditor’s ChoiceArticle

Microwave-Assisted Extraction of Phenolic Compounds from Spent Coffee Grounds. Process Optimization Applying Design of Experiments

by

José P. Coelho

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Maria P. Robalo

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Stanislava Boyadzhieva

and

Roumiana P. Stateva

Molecules 2021, 26(23), 7320; https://doi.org/10.3390/molecules26237320 - 02 Dec 2021

Cited by 6 | Viewed by 2096

Abstract

In this study, sustainable technology microwave-assisted extraction (MAE) in association with green solvents was applied to recover phenolic compounds from spent coffee grounds (SCGs). A design of experiments (DOE) was used for process optimization. Initially, a 2⁴⁻¹ two level Fractional Factorial Design [...] Read more.

In this study, sustainable technology microwave-assisted extraction (MAE) in association with green solvents was applied to recover phenolic compounds from spent coffee grounds (SCGs). A design of experiments (DOE) was used for process optimization. Initially, a 2⁴⁻¹ two level Fractional Factorial Design was used and ratios “solvent to solute” and “ethanol to water” were identified as the significant experimental factors. Consequently, Central Composite Design (CCD) was applied to analyze the effects of the significant variables on the response yield, total polyphenols content (TPC), and antioxidant activity (AA) by the DPPH assay method, and quadratic surfaces to optimize those responses were generated. The values of the significant factors of 16.7 (solvent/solute) and 68.9% (ethanol/water) were optimized simultaneously the yield (%) at 6.98 ± 0.27, TPC (mg GAE/g) at 117.7 ± 6.1, and AA (µmol TE/g) at 143.8 ± 8.6 and were in excellent agreement with those predicted from the CCD model. The variations of the compositions of the lipids, caffeine, pentacyclic diterpenes, and FAME as a function of the dominant factor % ethanol in the solvent mixture were analyzed by applying NMR and GC-FID, and the results obtained confirmed their determinative significance. Full article

(This article belongs to the Collection Ultrasound- and Microwave-Assisted Extraction of Bioactive Compounds)

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Open AccessEditor’s ChoiceReview

Synthesis and Applications of Carbohydrate-Based Organocatalysts

by

Elżbieta Wojaczyńska

,

Franz Steppeler

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Dominika Iwan

,

Marie-Christine Scherrmann

and

Alberto Marra

Molecules 2021, 26(23), 7291; https://doi.org/10.3390/molecules26237291 - 30 Nov 2021

Cited by 4 | Viewed by 3697

Abstract

Organocatalysis is a very useful tool for the asymmetric synthesis of biologically or pharmacologically active compounds because it avoids the use of noxious metals, which are difficult to eliminate from the target products. Moreover, in many cases, the organocatalysed reactions can be performed [...] Read more.

Organocatalysis is a very useful tool for the asymmetric synthesis of biologically or pharmacologically active compounds because it avoids the use of noxious metals, which are difficult to eliminate from the target products. Moreover, in many cases, the organocatalysed reactions can be performed in benign solvents and do not require anhydrous conditions. It is well-known that most of the above-mentioned reactions are promoted by a simple aminoacid, l-proline, or, to a lesser extent, by the more complex cinchona alkaloids. However, during the past three decades, other enantiopure natural compounds, the carbohydrates, have been employed as organocatalysts. In the present exhaustive review, the detailed preparation of all the sugar-based organocatalysts as well as their catalytic properties are described. Full article

(This article belongs to the Section Organic Chemistry)

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Open AccessEditor’s ChoiceArticle

Substituted Aryl Benzylamines as Potent and Selective Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 3

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Molecules 2021, 26(23), 7166; https://doi.org/10.3390/molecules26237166 - 26 Nov 2021

Cited by 1 | Viewed by 2271

Abstract

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective [...] Read more.

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC₅₀ 17β-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC₅₀ values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC₅₀ of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC₅₀ of 74 nM. Racemic C-allyl derivative 26 (IC₅₀ of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC₅₀ of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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Open AccessEditor’s ChoiceArticle

In Vitro and In Silico Interaction Studies with Red Wine Polyphenols against Different Proteins from Human Serum

by

Raja Mohamed Beema Shafreen

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Selvaraj Alagu Lakshmi

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Shunmugiah Karutha Pandian

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and

Molecules 2021, 26(21), 6686; https://doi.org/10.3390/molecules26216686 - 05 Nov 2021

Cited by 5 | Viewed by 2031

Abstract

Previous reports have shown that consumption of wine has several health benefits; however, there are different types of wine. In the present study, red wines were investigated for their compositions of active ingredients. The interaction of each component in terms of its binding [...] Read more.

Previous reports have shown that consumption of wine has several health benefits; however, there are different types of wine. In the present study, red wines were investigated for their compositions of active ingredients. The interaction of each component in terms of its binding mode with different serum proteins was unraveled, and the components were implicated as drug candidates in clinical settings. Overall, the study indicates that red wines have a composition of flavonoids, non-flavonoids, and phenolic acids that can interact with the key regions of proteins to enhance their biological activity. Among them, rutin, resveratrol, and tannic acid have shown good binding affinity and possess beneficial properties that can enhance their role in clinical applications. Full article

(This article belongs to the Special Issue Phenolic Compounds in Food: Characterization and Health Benefits)

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Open AccessEditor’s ChoiceArticle

Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro

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Carole J. R. Bataille

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Molecules 2021, 26(21), 6648; https://doi.org/10.3390/molecules26216648 - 02 Nov 2021

Viewed by 2105

Abstract

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional [...] Read more.

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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Open AccessEditor’s ChoiceReview

Recent Advances in the Synthesis of Polyamine Derivatives and Their Applications

by

Artemiy Nichugovskiy

,

Gian Cesare Tron

and

Mikhail Maslov

Molecules 2021, 26(21), 6579; https://doi.org/10.3390/molecules26216579 - 30 Oct 2021

Cited by 4 | Viewed by 2829

Abstract

Biogenic polyamines (PAs) are involved in the growth and development of normal cells, and their intracellular concentration is stable. The concentration of PAs in cancer cells is significantly increased to promote and sustain their rapid proliferation. Over the years, synthetic PAs, which differ [...] Read more.

Biogenic polyamines (PAs) are involved in the growth and development of normal cells, and their intracellular concentration is stable. The concentration of PAs in cancer cells is significantly increased to promote and sustain their rapid proliferation. Over the years, synthetic PAs, which differ in their structure, have demonstrated high antitumor activity and are involved in clinical trials. The chemical synthesis of PAs and their conjugates require the correct choice of synthetic pathways—methods for constructing conjugates and the orthogonal protection of amino groups. The most common methods of synthesis of PA conjugates are acylation of regioselectively protected PAs or their alkylation under the conditions of the Fukuyama reaction. One of the most promising methods of PA synthesis is the use of a multicomponent Ugi reaction, which allows various PAs to be obtained in high yields. In this review, we describe and analyze various approaches that are used in the synthesis of polyamines and their conjugates. Full article

(This article belongs to the Special Issue Polyamine Drug Discovery)

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Open AccessEditor’s ChoiceArticle

Structural Characterization of Unusual Fatty Acid Methyl Esters with Double and Triple Bonds Using HPLC/APCI-MS² with Acetonitrile In-Source Derivatization

by

Petra Horká

,

Vladimír Vrkoslav

,

Jiří Kindl

,

Karolina Schwarzová-Pecková

and

Josef Cvačka

Molecules 2021, 26(21), 6468; https://doi.org/10.3390/molecules26216468 - 26 Oct 2021

Cited by 1 | Viewed by 2267

Abstract

Double and triple bonds have significant effects on the biological activities of lipids. Determining multiple bond positions in their molecules by mass spectrometry usually requires chemical derivatization. This work presents an HPLC/MS method for pinpointing the double and triple bonds in fatty acids. [...] Read more.

Double and triple bonds have significant effects on the biological activities of lipids. Determining multiple bond positions in their molecules by mass spectrometry usually requires chemical derivatization. This work presents an HPLC/MS method for pinpointing the double and triple bonds in fatty acids. Fatty acid methyl esters were separated by reversed-phase HPLC with an acetonitrile mobile phase. In the APCI source, acetonitrile formed reactive species, which added to double and triple bonds to form [M + C₃H₅N]^+• ions. Their collisional activation in an ion trap provided fragments helpful in localizing the multiple bond positions. This approach was applied to fatty acids with isolated, cumulated, and conjugated double bonds and triple bonds. The fatty acids were isolated from the fat body of early-nesting bumblebee Bombus pratorum and seeds or seed oils of Punicum granatum, Marrubium vulgare, and Santalum album. Using the method, the presence of the known fatty acids was confirmed, and new ones were discovered. Full article

(This article belongs to the Special Issue Derivatization in Analytical Chemistry)

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Open AccessEditor’s ChoiceArticle

Monascin and Ankaflavin of Monascus purpureus Prevent Alcoholic Liver Disease through Regulating AMPK-Mediated Lipid Metabolism and Enhancing Both Anti-Inflammatory and Anti-Oxidative Systems

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Molecules 2021, 26(20), 6301; https://doi.org/10.3390/molecules26206301 - 18 Oct 2021

Cited by 11 | Viewed by 2886

Abstract

Alcohol metabolism causes an excessive accumulation of liver lipids and inflammation, resulting in liver damage. The yellow pigments monascin (MS) and ankaflavin (AK) of Monascus purpureus-fermented rice were proven to regulate ethanol-induced damage in HepG2 cells, but the complete anti-inflammatory and anti-fatty [...] Read more.

Alcohol metabolism causes an excessive accumulation of liver lipids and inflammation, resulting in liver damage. The yellow pigments monascin (MS) and ankaflavin (AK) of Monascus purpureus-fermented rice were proven to regulate ethanol-induced damage in HepG2 cells, but the complete anti-inflammatory and anti-fatty liver mechanisms in the animal model are still unclear. This study explored the roles of MS and AK in improving alcoholic liver injury. MS and AK were simultaneously fed to evaluate their effects and mechanisms in C57BL/6J mice fed the Lieber–DeCarli liquid alcohol diet for 6 weeks. The results indicated that MS and AK significantly reduced the serum aspartate aminotransferase and alanine aminotransferase activity, as well as the total liver cholesterol and triglyceride levels. The histopathological results indicated that MS and AK prevented lipid accumulation in the liver. MS and AK effectively enhanced the activity of antioxidant enzymes and reduced the degree of lipid peroxidation; AK was particularly effective and exhibited a superior preventive effect against alcoholic liver injury and fatty liver. In addition to inhibiting the phosphorylation of the MAPK family, MS and AK directly reduced TNF-α, IL-6, and IL-1β levels, thereby reducing NF-κB and its downstream iNOS and COX-2 expressions, as well as increasing PPAR-γ, Nrf-2, and HO-1 expressions to prevent liver damage. MS and AK also directly reduced TNF-α, IL-6, and IL-1β expression, thereby reducing the production of NF-κB and its downstream iNOS and COX-2, and increasing PPAR-γ, Nrf-2, and HO-1 expressions, preventing alcohol damage to the liver. Full article

(This article belongs to the Special Issue Functional Food and Their Pharmaceutical Properties)

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Open AccessEditor’s ChoiceArticle

Synthesis and Anti-HIV Activity of a Novel Series of Isoquinoline-Based CXCR4 Antagonists

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Mastaneh Safarnejad Shad

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Molecules 2021, 26(20), 6297; https://doi.org/10.3390/molecules26206297 - 18 Oct 2021

Cited by 1 | Viewed by 1678

Abstract

An expansion of the structure–activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 affinity and antagonism in competition binding and calcium [...] Read more.

An expansion of the structure–activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 affinity and antagonism in competition binding and calcium mobilization assays, respectively. In addition, the anti-HIV activity of all analogues was determined. All compounds showed excellent activity, with compound 24c being the most promising one, since it displayed consistently low nanomolar activity in the various assays. Full article

(This article belongs to the Special Issue Successfully Fighting Viruses with Love for Chemistry: A Commemorative Issue in Honor of Prof. Dr. Erik De Clercq on the Occasion of His 80th Anniversary)

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Open AccessEditor’s ChoiceArticle

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

by

Douglas B. Kell

Molecules 2021, 26(18), 5629; https://doi.org/10.3390/molecules26185629 - 16 Sep 2021

Cited by 9 | Viewed by 5567

Abstract

Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real [...] Read more.

Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport “phospholipid bilayer transport is negligible”. Full article

(This article belongs to the Special Issue Transporter-Mediated Drug Delivery)

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Open AccessFeature PaperEditor’s ChoiceReview

Breath Biomarkers in Diagnostic Applications

by

Y Lan Pham

and

Jonathan Beauchamp

Molecules 2021, 26(18), 5514; https://doi.org/10.3390/molecules26185514 - 11 Sep 2021

Cited by 15 | Viewed by 5166

Abstract

The detection of chemical compounds in exhaled human breath presents an opportunity to determine physiological state, diagnose disease or assess environmental exposure. Recent advancements in metabolomics research have led to improved capabilities to explore human metabolic profiles in breath. Despite some notable challenges [...] Read more.

The detection of chemical compounds in exhaled human breath presents an opportunity to determine physiological state, diagnose disease or assess environmental exposure. Recent advancements in metabolomics research have led to improved capabilities to explore human metabolic profiles in breath. Despite some notable challenges in sampling and analysis, exhaled breath represents a desirable medium for metabolomics applications, foremost due to its non-invasive, convenient and practically limitless availability. Several breath-based tests that target either endogenous or exogenous gas-phase compounds are currently established and are in practical and/or clinical use. This review outlines the concept of breath analysis in the context of these unique tests and their applications. The respective breath biomarkers targeted in each test are discussed in relation to their physiological production in the human body and the development and implementation of the associated tests. The paper concludes with a brief insight into prospective tests and an outlook of the future direction of breath research. Full article

(This article belongs to the Special Issue Theme Issue Honoring Professor Dr. Bogusław Buszewski on His 70th Birthday:"Separation Sciences & Related Techniques")

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Open AccessEditor’s ChoiceArticle

Nucleus-Independent Chemical Shift (NICS) as a Criterion for the Design of New Antifungal Benzofuranones

by

María de los Ángeles Zermeño-Macías

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Marco Martín González-Chávez

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Francisco Méndez

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Arlette Richaud

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Rodolfo González-Chávez

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Luis Enrique Ojeda-Fuentes

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Perla del Carmen Niño-Moreno

and

Roberto Martínez

Molecules 2021, 26(16), 5078; https://doi.org/10.3390/molecules26165078 - 21 Aug 2021

Cited by 2 | Viewed by 2151

Abstract

The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of [...] Read more.

The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p < 0.05); when aromaticity increased, the antifungal activity decreased for series I and increased for series II. To verify the validity of the obtained equations, a new set of 44 benzofuran-4-ones was designed by replacing the nitrogen atom of the five-membered ring with oxygen in indol-4-ones. The NICS(0) and NICS(1) of benzofuran-4-ones were calculated and used to predict their biological activities using the previous equations. A set of 10 benzofuran-4-ones was synthesized and tested in eight human pathogenic fungi, showing the validity of the equations. The minimum inhibitory concentration (MIC) in yeasts was 31.25 µg·mL^–1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 µg·mL^–1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity. Full article

(This article belongs to the Special Issue Chemical Bonding: A Commemorative Special Issue Honoring Professor Linus Pauling)

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Open AccessEditor’s ChoiceArticle

Detection of 4a,5-dihydropravastatin as Impurity in the Cholesterol Lowering Drug Pravastatin

by

Wibo B. van Scheppingen

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Peter P. Lankhorst

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Marcus Hans

and

Marco A. van den Berg

Molecules 2021, 26(15), 4685; https://doi.org/10.3390/molecules26154685 - 03 Aug 2021

Viewed by 1580

Abstract

Dihydro analogues are known byproducts of the fermentative production of statins and cannot be detected with existing pharmacopoeia analysis methods. We detected dihydropravastatin in most commercial formulations of pravastatin with LC-MS, in some cases in levels requiring identification. In fermentation broth samples of [...] Read more.

Dihydro analogues are known byproducts of the fermentative production of statins and cannot be detected with existing pharmacopoeia analysis methods. We detected dihydropravastatin in most commercial formulations of pravastatin with LC-MS, in some cases in levels requiring identification. In fermentation broth samples of the single step production of pravastatin, we detected and identified for the first time 4a,5-dihydropravastatin, and confirmed that after several recrystallization steps this impurity can be fully removed from the pravastatin powder. Full article

(This article belongs to the Special Issue Drug Analysis in Pharmaceutical Development and Drug Manufacturing)

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Open AccessEditor’s ChoiceArticle

Operando Raman Shift Replaces Current in Electrochemical Analysis of Li-ion Batteries: A Comparative Study

by

Mariusz Radtke

and

Christian Hess

Molecules 2021, 26(15), 4667; https://doi.org/10.3390/molecules26154667 - 01 Aug 2021

Cited by 3 | Viewed by 2336

Abstract

Li-rich and catalytically active

γ

-

L i_{x} V_{2} O_{5}

(x = 1.48) was investigated as a cathode for its heterogeneous charge transfer kinetics. Using a specially designed two-electrode system lithium half cell, Butler–Volmer analysis was performed, and Raman spectra [...] Read more.

Li-rich and catalytically active

γ

-

L i_{x} V_{2} O_{5}

(x = 1.48) was investigated as a cathode for its heterogeneous charge transfer kinetics. Using a specially designed two-electrode system lithium half cell, Butler–Volmer analysis was performed, and Raman spectra were acquired in 18 mV intervals. A direct correlation was observed between the Raman shift of the active modes

A_{g}

,

B_{g}

,

A_{u}

, and

B_{u}

, and the development of the Faraday current at the working electrode. The Raman intensity and the Raman shift were implemented to replace the current in a Tafel plot used for the analysis of Butler–Volmer kinetics. Striking similarities in the charge transfer proportionality constants

α

were found for current and Raman-based analysis. The potential of this new method of Raman-aided electrochemical detection at the diffraction limit is discussed. Full article

(This article belongs to the Special Issue Cutting-Edge Physical Chemistry Research in Europe)

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Open AccessEditor’s ChoiceArticle

Cyanovinylation of Aldehydes: Organocatalytic Multicomponent Synthesis of Conjugated Cyanomethyl Vinyl Ethers

by

Samuel Delgado-Hernández

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Fernando García-Tellado

and

David Tejedor

Molecules 2021, 26(14), 4120; https://doi.org/10.3390/molecules26144120 - 06 Jul 2021

Cited by 1 | Viewed by 1857

Abstract

A novel organocatalytic multicomponent cyanovinylation of aldehydes was designed for the synthesis of conjugated cyanomethyl vinyl ethers. The reaction was implemented for the synthesis of a 3-substituted 3-(cyanomethoxy)acrylates, using aldehydes as substrates, acetone cyanohydrin as the cyanide anion source, and methyl propiolate as [...] Read more.

A novel organocatalytic multicomponent cyanovinylation of aldehydes was designed for the synthesis of conjugated cyanomethyl vinyl ethers. The reaction was implemented for the synthesis of a 3-substituted 3-(cyanomethoxy)acrylates, using aldehydes as substrates, acetone cyanohydrin as the cyanide anion source, and methyl propiolate as the source of the vinyl component. The multicomponent reaction is catalyzed by N-methyl morpholine (2.5 mol%) to deliver the 3-(cyanomethoxy)acrylates in excellent yields and with preponderance of the E-isomer. The multicomponent reaction manifold is highly tolerant to the structure and composition of the aldehyde (aliphatic, aromatic, heteroaromatics), and it is instrumentally simple (one batch, open atmospheres), economic (2.5 mol% catalyst, stoichiometric reagents), environmentally friendly (no toxic waste), and sustainable (easy scalability). Full article

(This article belongs to the Special Issue New Approach in Multicomponent Reactions)

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Open AccessEditor’s ChoiceReview

Melatonin, Its Metabolites and Their Interference with Reactive Nitrogen Compounds

by

Rüdiger Hardeland

Molecules 2021, 26(13), 4105; https://doi.org/10.3390/molecules26134105 - 05 Jul 2021

Cited by 13 | Viewed by 2857

Abstract

Melatonin and several of its metabolites are interfering with reactive nitrogen. With the notion of prevailing melatonin formation in tissues that exceeds by far the quantities in blood, metabolites come into focus that are poorly found in the circulation. Apart from their antioxidant [...] Read more.

Melatonin and several of its metabolites are interfering with reactive nitrogen. With the notion of prevailing melatonin formation in tissues that exceeds by far the quantities in blood, metabolites come into focus that are poorly found in the circulation. Apart from their antioxidant actions, both melatonin and N¹-acetyl-5-methoxykynuramine (AMK) downregulate inducible and inhibit neuronal NO synthases, and additionally scavenge NO. However, the NO adduct of melatonin redonates NO, whereas AMK forms with NO a stable product. Many other melatonin metabolites formed in oxidative processes also contain nitrosylatable sites. Moreover, AMK readily scavenges products of the CO₂-adduct of peroxynitrite such as carbonate radicals and NO₂. Protein AMKylation seems to be involved in protective actions. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms II)

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Open AccessEditor’s ChoiceReview

Supramolecular Chemistry: Host–Guest Molecular Complexes

by

Sadaf Bashir Khan

and

Shern-Long Lee

Molecules 2021, 26(13), 3995; https://doi.org/10.3390/molecules26133995 - 30 Jun 2021

Cited by 21 | Viewed by 4552

Abstract

In recent times, researchers have emphasized practical approaches for capturing coordinated and selective guest entrap. The physisorbed nanoporous supramolecular complexes have been widely used to restrain various guest species on compact supporting surfaces. The host–guest (HG) interactions in two-dimensional (2D) permeable porous linkages [...] Read more.

In recent times, researchers have emphasized practical approaches for capturing coordinated and selective guest entrap. The physisorbed nanoporous supramolecular complexes have been widely used to restrain various guest species on compact supporting surfaces. The host–guest (HG) interactions in two-dimensional (2D) permeable porous linkages are growing expeditiously due to their future applications in biocatalysis, separation technology, or nanoscale patterning. The different crystal-like nanoporous network has been acquired to enclose and trap guest molecules of various dimensions and contours. The host centers have been lumped together via noncovalent interactions (such as hydrogen bonds, van der Waals (vdW) interactions, or coordinate bonds). In this review article, we enlighten and elucidate recent progress in HG chemistry, explored via scanning tunneling microscopy (STM). We summarize the synthesis, design, and characterization of typical HG structural design examined on various substrates, under ambient surroundings at the liquid-solid (LS) interface, or during ultrahigh vacuum (UHV). We emphasize isoreticular complexes, vibrant HG coordination, or hosts functional cavities responsive to the applied stimulus. Finally, we critically discuss the significant challenges in advancing this developing electrochemical field. Full article

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Open AccessEditor’s ChoiceArticle

Analysis of Volatile Molecules Present in the Secretome of the Fungal Pathogen Candida glabrata

by

Juan Ernesto López-Ramos

,

Elihú Bautista

,

Guadalupe Gutiérrez-Escobedo

,

Gabriela Mancilla-Montelongo

,

Irene Castaño

,

Marco Martín González-Chávez

and

Alejandro De Las Peñas

Molecules 2021, 26(13), 3881; https://doi.org/10.3390/molecules26133881 - 25 Jun 2021

Cited by 1 | Viewed by 1818

Abstract

Candida albicans, Candida glabrata, Candida parapsilosis and Candida tropicalis are the four most common human fungal pathogens isolated that can cause superficial and invasive infections. It has been shown that specific metabolites present in the secretomes of these fungal pathogens are important [...] Read more.

Candida albicans, Candida glabrata, Candida parapsilosis and Candida tropicalis are the four most common human fungal pathogens isolated that can cause superficial and invasive infections. It has been shown that specific metabolites present in the secretomes of these fungal pathogens are important for their virulence. C. glabrata is the second most common isolate world-wide and has an innate resistance to azoles, xenobiotics and oxidative stress that allows this fungal pathogen to evade the immune response and persist within the host. Here, we analyzed and compared the C. glabrata secretome with those of C. albicans, C. parapsilosis, C. tropicalis and the non-pathogenic yeast Saccharomyces cerevisiae. In C. glabrata, we identified a different number of metabolites depending on the growth media: 12 in synthetic complete media (SC), 27 in SC-glutamic acid and 23 in rich media (YPD). C. glabrata specific metabolites are 1-dodecene (0.09 ± 0.11%), 2,5-dimethylundecane (1.01 ± 0.19%), 3,7-dimethyldecane (0.14 ± 0.15%), and octadecane (0.4 ± 0.53%). The metabolites that are shared with C. albicans, C. glabrata, C. parapsilosis, C. tropicalis and S. cerevisiae are phenylethanol, which is synthesized from phenylalanine, and eicosane and nonanoic acid (identified as trimethylsilyl ester), which are synthesized from fatty acid metabolism. Phenylethanol is the most abundant metabolite in all fungi tested: 26.36 ± 17.42% (C. glabrata), 46.77 ± 15.58% (C. albicans), 49.76 ± 18.43% (C. tropicalis), 5.72 ± 0.66% (C. parapsilosis.) and 44.58 ± 27.91% (S. cerevisiae). The analysis of C. glabrata’s secretome will allow us to further our understanding of the possible role these metabolites could play in its virulence. Full article

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Open AccessEditor’s ChoiceArticle

Trends in the Use of Botanicals in Anti-Aging Cosmetics

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Marta Salvador Ferreira

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Maria Catarina Magalhães

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Rita Oliveira

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José Manuel Sousa-Lobo

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Isabel Filipa Almeida

Molecules 2021, 26(12), 3584; https://doi.org/10.3390/molecules26123584 - 11 Jun 2021

Cited by 21 | Viewed by 9024

Abstract

Botanical ingredients have been used for thousands of years in skincare for their convenience as well as the diversity and abundance in compounds with biological activity. Among these, polyphenols and especially flavonoids have gained increasing prominence due to their antioxidant and anti-inflammatory properties. [...] Read more.

Botanical ingredients have been used for thousands of years in skincare for their convenience as well as the diversity and abundance in compounds with biological activity. Among these, polyphenols and especially flavonoids have gained increasing prominence due to their antioxidant and anti-inflammatory properties. In this study, the most used botanical preparations in anti-aging products marketed in 2011 were determined. The analysis was repeated in 2018 for new and reformulated products. The scientific evidence for their application as active ingredients in anti-aging cosmetics and their flavonoid content was also compiled by searching in online scientific databases. Overall, in 2018, there was a noticeable increase in the use of botanical preparations in anti-aging cosmetics. However, the top three botanical species in both years were Vitis vinifera, Butyrospermum parkii, and Glycine soja, which is consistent with the greater amount of scientific evidence supporting their efficacy. Regarding the function of botanical preparations, there is a clear preference for DNA-protecting ingredients. The most prevalent flavonoids were flavan-3-ols, proanthocyanidins, and anthocyanins. This study provided an updated overview of the market trends regarding the use of botanicals in anti-aging products and documented the state of the art of scientific evidence for the most used plants. Full article

(This article belongs to the Special Issue Bioactive Flavonoids and Xanthones: From Bench to Industry. Pharmaceutical, Cosmetic and Industrial Applications)

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Open AccessEditor’s ChoiceReview

Synthesis and Reactivity of 3H-1,2-dithiole-3-thiones

by

Oleg A. Rakitin

Molecules 2021, 26(12), 3595; https://doi.org/10.3390/molecules26123595 - 11 Jun 2021

Cited by 9 | Viewed by 4028

Abstract

3H-1,2-Dithiole-3-thiones are among the best studied classes of polysulfur-containing heterocycles due to the almost explosive recent interest in these compounds as sources of hydrogen sulfide as an endogenously produced gaseous signaling molecule. This review covers the recent developments in the synthesis [...] Read more.

3H-1,2-Dithiole-3-thiones are among the best studied classes of polysulfur-containing heterocycles due to the almost explosive recent interest in these compounds as sources of hydrogen sulfide as an endogenously produced gaseous signaling molecule. This review covers the recent developments in the synthesis of these heterocycles, including both well-known procedures and important novel transformations for building the 1,2-dithiole-3-thione ring. Diverse ring transformations of 3H-1,2-dithiole-3-thiones into various heterocyclic systems through 1,3-dipolar cycloaddition, replacement of one or two sulfur atoms to form carbon- and carbon-nitrogen containing moieties, and other unexpected reactions are considered. Full article

(This article belongs to the Special Issue Polysulfur- and Sulfur-Nitrogen Heterocycles)

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Open AccessFeature PaperEditor’s ChoiceArticle

The Physico-Chemical Properties of Glipizide: New Findings

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Molecules 2021, 26(11), 3142; https://doi.org/10.3390/molecules26113142 - 24 May 2021

Cited by 2 | Viewed by 4984

Abstract

The present work is a concrete example of how physico-chemical studies, if performed in depth, are crucial to understand the behavior of pharmaceutical solids and constitute a solid basis for the control of the reproducibility of the industrial batches. In particular, a deep [...] Read more.

The present work is a concrete example of how physico-chemical studies, if performed in depth, are crucial to understand the behavior of pharmaceutical solids and constitute a solid basis for the control of the reproducibility of the industrial batches. In particular, a deep study of the thermal behavior of glipizide, a hypoglycemic drug, was carried out with the aim of clarifying whether the recognition of its polymorphic forms can really be done on the basis of the endothermic peak that the literature studies attribute to the melting of the compound. A number of analytical techniques were used: thermal techniques (DSC, TGA), X-ray powder diffraction (XRPD), FT-IR spectroscopy and scanning electron microscopy (SEM). Great attention was paid to the experimental design and to the interpretation of the combined results obtained by all these techniques. We proved that the attribution of the endothermic peak shown by glipizide to its melting was actually wrong. The DSC peak is no doubt triggered by a decomposition process that involves gas evolution (cyclohexanamine and carbon dioxide) and formation of 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide, which remains as decomposition residue. Thermal treatments properly designed and the combined use of DSC with FT-IR and XRPD led to identifying a new polymorphic form of 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide, which is obtained by crystallization from the melt. Hence, our results put into evidence that the check of the polymorphic form of glipizide cannot be based on the temperature values of the DSC peak, since such a peak is due to a decomposition process whose Tonset value is strongly affected by the particle size. Kinetic studies of the decomposition process show the high stability of solid glipizide at room temperature. Full article

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Physical Chemistry Section of Molecules)

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Open AccessEditor’s ChoiceArticle

A Combined Experimental and Computational Study of Halogen and Hydrogen Bonding in Molecular Salts of 5-Bromocytosine

by

Massimiliano Aschi

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Giorgia Toto Brocchi

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Gustavo Portalone

Molecules 2021, 26(11), 3111; https://doi.org/10.3390/molecules26113111 - 23 May 2021

Cited by 1 | Viewed by 2967

Abstract

Although natural or artificial modified pyrimidine nucleobases represent important molecules with valuable properties as constituents of DNA and RNA, no systematic analyses of the structural aspects of bromo derivatives of cytosine have appeared so far in the literature. In view of the biochemical [...] Read more.

Although natural or artificial modified pyrimidine nucleobases represent important molecules with valuable properties as constituents of DNA and RNA, no systematic analyses of the structural aspects of bromo derivatives of cytosine have appeared so far in the literature. In view of the biochemical and pharmaceutical relevance of these compounds, six different crystals containing proton-transfer derivatives of 5-bromocytosine are prepared and analyzed in the solid-state by single crystal X-ray diffraction. All six compounds are organic salts, with proton transfer occurring to the N_imino atom of the pyridine ring. Experimental results are then complemented with Hirshfeld surface analysis to quantitively evaluate the contribution of different intermolecular interactions in the crystal packing. Furthermore, theoretical calculations, based on different arrangements of molecules extracted from the crystal structure determinations, are carried out to analyze the formation mechanism of halogen bonds (XBs) in these compounds and provide insights into the nature and strength of the observed interactions. The results show that the supramolecular architectures of the six molecular salts involve extensive classical intermolecular hydrogen bonds. However, in all but one proton-transfer adducts, weak to moderate XBs are revealed by C–Br^…O short contacts between the bromine atom in the fifth position, which acts as XB donor (electron acceptor). Moreover, the lone pair electrons of the oxygen atom of adjacent pyrimidine nucleobases and/or counterions or water molecules, which acts as XB acceptor (electron donor). Full article

(This article belongs to the Special Issue Beyond the Canonical DNA Double-Helix: Supramolecular Assemblies of Chemically Modified Nucleic Acids and their Applications)

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Open AccessEditor’s ChoiceReview

Microwave-Assisted Preparation of Luminescent Inorganic Materials: A Fast Route to Light Conversion and Storage Phosphors

by

José Miranda de Carvalho

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Cássio Cardoso Santos Pedroso

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Matheus Salgado de Nichile Saula

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Maria Claudia França Cunha Felinto

and

Hermi Felinto de Brito

Molecules 2021, 26(10), 2882; https://doi.org/10.3390/molecules26102882 - 13 May 2021

Cited by 7 | Viewed by 3373

Abstract

Luminescent inorganic materials are used in several technological applications such as light-emitting displays, white LEDs for illumination, bioimaging, and photodynamic therapy. Usually, inorganic phosphors (e.g., complex oxides, silicates) need high temperatures and, in some cases, specific atmospheres to be formed or to obtain [...] Read more.

Luminescent inorganic materials are used in several technological applications such as light-emitting displays, white LEDs for illumination, bioimaging, and photodynamic therapy. Usually, inorganic phosphors (e.g., complex oxides, silicates) need high temperatures and, in some cases, specific atmospheres to be formed or to obtain a homogeneous composition. Low ionic diffusion and high melting points of the precursors lead to long processing times in these solid-state syntheses with a cost in energy consumption when conventional heating methods are applied. Microwave-assisted synthesis relies on selective, volumetric heating attributed to the electromagnetic radiation interaction with the matter. The microwave heating allows for rapid heating rates and small temperature gradients yielding homogeneous, well-formed materials swiftly. Luminescent inorganic materials can benefit significantly from the microwave-assisted synthesis for high homogeneity, diverse morphology, and rapid screening of different compositions. The rapid screening allows for fast material investigation, whereas the benefits of enhanced homogeneity include improvement in the optical properties such as quantum yields and storage capacity. Full article

(This article belongs to the Special Issue The Application of Microwave Technology in Chemistry)

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Open AccessEditor’s ChoiceArticle

Selenoxide Elimination Triggers Enamine Hydrolysis to Primary and Secondary Amines: A Combined Experimental and Theoretical Investigation

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Alessandra Gianoncelli

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Giuseppe Zagotto

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Laura Orian

Molecules 2021, 26(9), 2770; https://doi.org/10.3390/molecules26092770 - 08 May 2021

Cited by 4 | Viewed by 2453

Abstract

We discuss a novel selenium-based reaction mechanism consisting in a selenoxide elimination-triggered enamine hydrolysis. This one-pot model reaction was studied for a set of substrates. Under oxidative conditions, we observed and characterized the formation of primary and secondary amines as elimination products of [...] Read more.

We discuss a novel selenium-based reaction mechanism consisting in a selenoxide elimination-triggered enamine hydrolysis. This one-pot model reaction was studied for a set of substrates. Under oxidative conditions, we observed and characterized the formation of primary and secondary amines as elimination products of such compounds, paving the way for a novel strategy to selectively release bioactive molecules. The underlying mechanism was investigated using NMR, mass spectrometry and density functional theory (DFT). Full article

(This article belongs to the Special Issue From a Molecule to a Drug: Chemical Features Enhancing Pharmacological Potential)

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Open AccessEditor’s ChoiceArticle

Predicting Accurate Lead Structures for Screening Molecular Libraries: A Quantum Crystallographic Approach

by

Suman Kumar Mandal

and

Parthapratim Munshi

Molecules 2021, 26(9), 2605; https://doi.org/10.3390/molecules26092605 - 29 Apr 2021

Viewed by 2230

Abstract

Optimization of lead structures is crucial for drug discovery. However, the accuracy of such a prediction using the traditional molecular docking approach remains a major concern. Our study demonstrates that the employment of quantum crystallographic approach-counterpoise corrected kernel energy method (KEM-CP) can improve [...] Read more.

Optimization of lead structures is crucial for drug discovery. However, the accuracy of such a prediction using the traditional molecular docking approach remains a major concern. Our study demonstrates that the employment of quantum crystallographic approach-counterpoise corrected kernel energy method (KEM-CP) can improve the accuracy by and large. We select human aldose reductase at 0.66 Å, cyclin dependent kinase 2 at 2.0 Å and estrogen receptor β at 2.7 Å resolutions with active site environment ranging from highly hydrophilic to moderate to highly hydrophobic and several of their known ligands. Overall, the use of KEM-CP alongside the GoldScore resulted superior prediction than the GoldScore alone. Unlike GoldScore, the KEM-CP approach is neither environment-specific nor structural resolution dependent, which highlights its versatility. Further, the ranking of the ligands based on the KEM-CP results correlated well with that of the experimental IC₅₀ values. This computationally inexpensive yet simple approach is expected to ease the process of virtual screening of potent ligands, and it would advance the drug discovery research. Full article

(This article belongs to the Special Issue Chemical Bonding: A Commemorative Special Issue Honoring Professor Linus Pauling)

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Open AccessFeature PaperEditor’s ChoiceArticle

Synthesis of New Triazolopyrazine Antimalarial Compounds

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Molecules 2021, 26(9), 2421; https://doi.org/10.3390/molecules26092421 - 21 Apr 2021

Cited by 2 | Viewed by 3005

Abstract

A radical approach to late-stage functionalization using photoredox and Diversinate^™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of [...] Read more.

A radical approach to late-stage functionalization using photoredox and Diversinate^™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC₅₀ values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM. Full article

(This article belongs to the Special Issue Organic Synthesis in Drug Discovery)

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Open AccessEditor’s ChoiceArticle

New Bioconjugated Technetium and Rhenium Folates Synthesized by Transmetallation Reaction with Zinc Derivatives

by

Jordi Borràs

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Julie Foster

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Roxana Kashani

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Laura Meléndez-Alafort

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Jane Sosabowski

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Joan Suades

and

Ramon Barnadas-Rodríguez

Molecules 2021, 26(8), 2373; https://doi.org/10.3390/molecules26082373 - 19 Apr 2021

Cited by 1 | Viewed by 1633

Abstract

The zinc dithiocarbamates functionalized with folic acid 2_Zn and 3_Zn were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (1_Zn). Zinc complexes 2_Zn and 3_Zn show very [...] Read more.

The zinc dithiocarbamates functionalized with folic acid 2_Zn and 3_Zn were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (1_Zn). Zinc complexes 2_Zn and 3_Zn show very low solubilities in water, making them useful for preparing Tc-99m radiopharmaceuticals with a potentially high molar activity. Thus, the transmetallation reaction in water medium between the zinc complexes 2_Zn or 3_Zn and the cation fac-[^99mTc(H₂O)₃(CO)₃]⁺, in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes fac-[^99mTc(CO)₃(SS)(P)] bioconjugated to folic acid (2_Tc and 3_Tc). In spite of the low solubility of 2_Zn and 3_Zn in water, the reaction yield is higher than 95%, and the excess zinc reagent is easily removed by centrifugation. The Tc-99m complexes were characterized by comparing their HPLC with those of the homologous rhenium complexes (2_Re and 3_Re) previously synthesized and characterized by standard methods. Preliminary in vivo studies with 2_Tc and 3_Tc indicate low specific binding to folate receptors. In summary, Tc-99m folates 2_Tc and 3_Tc were prepared in high yields, using a one-pot transmetallation reaction with low soluble zinc dithiocarbamates (>1 ppm), at moderate temperature, without needing a subsequent purification step. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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