Editor’s Choice Articles

The mechanisms of retro-Diels–Alder fragmentation of luteolin are studied theoretically using the Density Functional Theory method (B3LYP hybrid functional) together with the 6-311++G(d,p) basis set and supported by electrospray ionization tandem mass spectrometry (ESI-MS) results. The reaction paths leading to the formation of ^1,3A⁻ and ^1,3B⁻ fragment ions observed as the main spectral features in the ESI-MS spectrum are described and discussed, including the structures of the transition states and intermediate products. The heights of the activation energy barriers which have to be overcome along the reaction paths corresponding to 1,3-retrocyclization cleavage of the ionized luteolin are predicted to span the 69–94 kcal/mol range (depending on the initial isomeric structure) for the concerted retrocyclization mechanism and the 60–89 kcal/mol (first barrier) and 24–52 kcal/mol (second barrier) barriers for the stepwise mechanism (also depending on the initial isomeric structure). It is also demonstrated that the final fragmentation products (^1,3A⁻ and ^1,3B⁻) are in fact represented by various isomeric systems which are not experimentally distinguishable. In addition, the absence of the spectral feature corresponding to the [M-B]⁻ fragment ion formed by the rupture of the C-C bond connecting luteolin’s B and C rings (which does not occur during the ESI-MS experiment) is explained by much larger energy barriers predicted for such a process. Full article

Fluorine is a common substituent in medicinal chemistry and is found in up to 50% of the most profitable drugs. In this study, a statistical analysis of the nature, geometry, and frequency of hydrogen bonds (HBs) formed between the aromatic and aliphatic C–F groups of small molecules and biological targets found in the Protein Data Bank (PDB) repository was presented. Interaction energies were calculated for those complexes using three different approaches. The obtained results indicated that the interaction energy of F-containing HBs is determined by the donor–acceptor distance and not by the angles. Moreover, no significant relationship between the energies of HBs with fluorine and the donor type was found, implying that fluorine is a weak HB acceptor for all types of HB donors. However, the statistical analysis of the PDB repository revealed that the most populated geometric parameters of HBs did not match the calculated energetic optima. In a nutshell, HBs containing fluorine are forced to form due to the stronger ligand–receptor neighboring interactions, which make fluorine the “donor’s last resort”. Full article

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular S_NAr or S_N2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010. Full article

Herein we report a practical method for the asymmetric transfer hydrogenation/dynamic kinetic resolution of N-Boc 3-fluoro-dihydrotetrahydroquinolin-4-ones into the corresponding cis-fluoro alcohols in 70–96% yields, up to 99:1 diastereomeric ratio (dr) and up to >99% ee (enantiomeric excess) by using the ruthenium complex Ts-DENEB and a formic acid/triethylamine (1:1) mixture as the hydrogen donor under mild conditions. Full article

Insufficient intake of beneficial food components into the human body is a major issue for many people. Among the strategies proposed to overcome this complication, colloid systems have been proven to offer successful solutions in many cases. The scientific community agrees that the production of colloid delivery systems is a good way to adequately protect and deliver nutritional components. In this review, we present the recent advances on bioactive phenolic compounds delivery mediated by colloid systems. As we are aware that this field is constantly evolving, we have focused our attention on the progress made in recent years in this specific field. To achieve this goal, structural and dynamic aspects of different colloid delivery systems, and the various interactions with two bioactive constituents, are presented and discussed. The choice of the appropriate delivery system for a given molecule depends on whether the drug is incorporated in an aqueous or hydrophobic environment. With this in mind, the aim of this evaluation was focused on two case studies, one representative of hydrophobic phenolic compounds and the other of hydrophilic ones. In particular, hydroxytyrosol was selected as a bioactive phenol with a hydrophilic character, while curcumin was selected as typical representative hydrophobic molecules. Full article

Accumulated preclinical and clinical data show that peripheral restricted opioids provide pain relief with reduced side effects. The peripherally acting opioid analgesic HS-731 is a potent dual μ-/δ-opioid receptor (MOR/DOR) full agonist, and a weak, partial agonist at the κ-opioid receptor (KOR). However, its binding mode at the opioid receptors remains elusive. Here, we present a comprehensive in silico evaluation of HS-731 binding at all opioid receptors. We provide insights into dynamic interaction patterns explaining the different binding and activity of HS-731 on the opioid receptors. For this purpose, we conducted docking, performed molecular dynamics (MD) simulations and generated dynamic pharmacophores (dynophores). Our results highlight two residues important for HS-731 recognition at the classical opioid receptors (MOR, DOR and KOR), particular the conserved residue 5.39 (K) and the non-conserved residue 6.58 (MOR: K, DOR: W and KOR: E). Furthermore, we assume a salt bridge between the transmembrane helices (TM) 5 and 6 via K227^5.39 and E297^6.58 to be responsible for the partial agonism of HS-731 at the KOR. Additionally, we experimentally demonstrated the absence of affinity of HS-731 to the nociceptin/orphanin FQ peptide (NOP) receptor. We consider the morphinan phenol Y130^3.33 responsible for this affinity lack. Y130^3.33 points deep into the NOP receptor binding pocket preventing HS-731 binding to the orthosteric binding pocket. These findings provide significant structural insights into HS-731 interaction pattern with the opioid receptors that are important for understanding the pharmacology of this peripheral opioid analgesic. Full article

The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case. Full article

d-metal oxides play a crucial role in numerous technological applications and show a great variety of magnetic properties. We have systematically investigated the structural properties, magnetic ground states, and fundamental electronic properties of 100 binary d-metal oxides using hybrid density functional methods and localized basis sets composed of Gaussian-type functions. The calculated properties are compared with experimental information in all cases where experimental data are available. The used PBE0 hybrid density functional method describes the structural properties of the studied d-metal oxides well, except in the case of molecular oxides with weak intermolecular forces between the molecular units. Empirical D3 dispersion correction does not improve the structural description of the molecular oxides. We provide a database of optimized geometries and magnetic ground states to facilitate future studies on the more complex properties of the binary d-metal oxides. Full article

Two new peroxosolvates of drug-like compounds were synthesized and studied by a combination of X-ray crystallographic, Raman spectroscopic methods, and periodic DFT computations. The enthalpies of H-bonds formed by hydrogen peroxide (H₂O₂) as a donor and an acceptor of protons were compared with the enthalpies of analogous H-bonds formed by water (H₂O) in isomorphic (isostructural) hydrates. The enthalpies of H-bonds formed by H₂O₂ as a proton donor turned out to be higher than the values of the corresponding H-bonds formed by H₂O. In the case of H₂O₂ as a proton acceptor in H-bonds, the ratio appeared reversed. The neutral O∙∙∙H-O/O∙∙∙H-N bonds formed by the lone electron pair of the oxygen atom of water were the strongest H-bonds in the considered crystals. In the paper, it was found out that the low-frequency Raman spectra of isomorphous crystalline hydrate and peroxosolvate of N-(5-Nitro-2-furfurylidene)-1-aminohydantoin are similar. As for the isostructural hydrate and peroxosolvate of the salt of protonated 2-amino-nicotinic acid and maleic acid monoanion, the Raman spectra are different. Full article

Histone deacetylases (HDACs) are a large family of epigenetic metalloenzymes that are involved in gene transcription and regulation, cell proliferation, differentiation, migration, and death, as well as angiogenesis. Particularly, disorders of the HDACs expression are linked to the development of many types of cancer and neurodegenerative diseases, making them interesting molecular targets for the design of new efficient drugs and imaging agents that facilitate an early diagnosis of these diseases. Thus, their selective inhibition or degradation are the basis for new therapies. This is supported by the fact that many HDAC inhibitors (HDACis) are currently under clinical research for cancer therapy, and the Food and Drug Administration (FDA) has already approved some of them. In this review, we will focus on the recent advances and latest discoveries of innovative strategies in the development and applications of compounds that demonstrate inhibitory or degradation activity against HDACs, such as PROteolysis-TArgeting Chimeras (PROTACs), tumor-targeted HDACis (e.g., folate conjugates and nanoparticles), and imaging probes (positron emission tomography (PET) and fluorescent ligands). Full article

Since the outbreak of SARS-CoV-2, numerous compounds against COVID-19 have been derived by computer-aided drug design (CADD) studies. They are valuable resources for the development of COVID-19 therapeutics. In this work, we reviewed these studies and analyzed 779 compounds against 16 target proteins from 181 CADD publications. We performed unified docking simulations and neck-to-neck comparison with the solved co-crystal structures. We computed their chemical features and classified these compounds, aiming to provide insights for subsequent drug design. Through detailed analyses, we recommended a batch of compounds that are worth further study. Moreover, we organized all the abundant data and constructed a freely available database, DrugDevCovid19, to facilitate the development of COVID-19 therapeutics. Full article

Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Multidrug resistance may be also related to antimicrobial drugs, and is known to be one of the most serious global public health threats of this century. Indeed, this phenomenon has increased both mortality and morbidity as a consequence of treatment failures and its incidence in healthcare costs. The large amounts of antibiotics used in human therapies, as well as for farm animals and even for fishes in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. It is not negligible that the ongoing COVID-19 pandemic may further contribute to antimicrobial resistance. In this paper, multidrug resistance and antimicrobial resistance are underlined, focusing on the therapeutic options to overcome these obstacles in drug treatments. Lastly, some recent studies on nanodrug delivery systems have been reviewed since they may represent a significant approach for overcoming resistance. Full article

Organometallic compounds are increasingly recognized as promising anticancer and antibiotic drug candidates. Among the transition metal ions investigated for these purposes, rhenium occupies a special role. Its tri- and dicarbonyl complexes, in particular, attract continuous attention due to their relative ease of preparation, stability and unique photophysical and luminescent properties that allow the combination of diagnostic and therapeutic purposes, thereby permitting, e.g., molecules to be tracked within cells. In this review, we discuss the anticancer and antibiotic properties of rhenium tri- and dicarbonyl complexes described in the last seven years, mainly in terms of their structural variations and in vitro efficacy. Given the abundant literature available, the focus is initially directed on tricarbonyl complexes of rhenium. Dicarbonyl species of the metal ion, which are slowly gaining momentum, are discussed in the second part in terms of future perspective for the possible developments in the field. Full article

Performing synthetic transformation using visible light as energy source, in the presence of a photocatalyst as a promoter, is currently of high interest, and oxidation reactions carried out under these conditions using oxygen as the final oxidant are particularly convenient from an environmental point of view. This review summarizes the recent developments achieved in the oxidative dehydrogenation of C–N and C–O bonds, leading to C=N and C=O bonds, respectively, using air or pure oxygen as oxidant and metal-free homogeneous or recyclable heterogeneous photocatalysts under visible light irradiation. Full article

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line. Full article

Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-WIN 55,212-2 complex, among which sites B, C, G and K are supported by the reported 3D structures of Class A GPCRs coupled with AMs. Applying our novel algorithm toolset-MCCS, we docked three known AMs of CB2 including Ec2la (C-2), trans-β-caryophyllene (TBC) and cannabidiol (CBD) to each site for further comparisons and quantified the potential binding residues in each allosteric binding site. Sequentially, we selected the most promising binding pose of C-2 in five allosteric sites to conduct the molecular dynamics (MD) simulations. Based on the results of docking studies and MD simulations, we suggest that site H is the most promising allosteric binding site. We plan to conduct bio-assay validations in the future. Full article

Recently, there has been a strong demand for technologies that use hydrogen as an energy carrier, instead of fossil fuels. Hence, new and effective hydrogen storage technologies are attracting increasing attention. Formic acid (FA) is considered an effective liquid chemical for hydrogen storage because it is easier to handle than solid or gaseous materials. This review presents recent advances in research into the development of homogeneous catalysts, primarily focusing on hydrogen generation by FA dehydrogenation. Notably, this review will aid in the development of useful catalysts, thereby accelerating the transition to a hydrogen-based society. Full article

An effective strategy has been developed for the photoredox-catalyzed decarboxylative addition of cyclic amino acids to both vinylogous amides and esters leading to uniquely substituted heterocycles. The additions take place exclusively trans to the substituent present on the dihydropyridone ring affording stereochemical control about the new carbon-carbon bond. These reactions are operationally simplistic and afford the desired products in good to excellent isolated yields. Full article

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

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

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

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

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

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

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

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

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

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

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

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

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

Li-rich and catalytically active $\gamma$-$L{i}_x{V}_2{O}_5$ (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 $\alpha$ 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

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

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

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

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

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

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

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

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

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

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

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

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

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

The aim of this work is to present an approach to enhance the dissolution of progestin medication, megestrol acetate (also known as MEGACE), for improving the dissolution rate and kinetic solubility by incorporating nano graphene oxide (nGO). An antisolvent precipitation process was investigated for nGO-drug composite preparation, where prepared composites showed crystalline properties that were similar to the pure drug but enhanced aqueous dispersibility and colloidal stability. To validate the efficient release profile of composite, in vitro dissolution testing was carried out using United States Pharmacopeia, USP-42 paddle method, with gastric pH (1.4) and intestinal pH (6.5) solutions to mimic in vivo conditions. Pure MA is practically insoluble (2 µg/mL at 37 °C). With the incorporation of nGO, it was possible to dissolve nearly 100% in the assay. With the incorporation of 1.0% of nGO, the time required to dissolve 50% and 80% of drug, namely T₅₀ and T₈₀, decreased from 138.0 min to 27.0 min, and the drug did not dissolve for 97.0 min in gastric media, respectively. Additionally, studies done in intestinal media have revealed T₅₀ did not dissolve for 92.0 min. This work shows promise in incorporating functionalized nanoparticles into the crystal lattice of poorly soluble drugs to improve dissolution rate. Full article

How life did originate and what is life, in its deepest foundation? The texture of life is known to be held by molecules and their chemical-physical laws, yet a thorough elucidation of the aforementioned questions still stands as a puzzling challenge for science. Focusing solely on molecules and their laws has indirectly consolidated, in the scientific knowledge, a mechanistic (reductionist) perspective of biology and medicine. This occurred throughout the long historical path of experimental science, affecting subsequently the onset of the many theses and speculations about the origin of life and its maintenance. Actually, defining what is life, asks for a novel epistemology, a ground on which living systems’ organization, whose origin is still questioned via chemistry, physics and even philosophy, may provide a new key to focus onto the complex nature of the human being. In this scenario, many issues, such as the role of information and water structure, have been long time neglected from the theoretical basis on the origin of life and marginalized as a kind of scenic backstage. On the contrary, applied science and technology went ahead on considering molecules as the sole leading components in the scenery. Water physics and information dynamics may have a role in living systems much more fundamental than ever expected. Can an organism be simply explained by a mechanistic view of its nature or we need “something else”? Probably, we can earn sound foundations about life by simply changing our prejudicial view about living systems simply as complex, highly ordered machines. In this manuscript we would like to reappraise many fundamental aspects of molecular and chemical biology and reading them through a new paradigm, which includes Prigogine’s dissipative structures and informational dissipation (Shannon dissipation). This would provide readers with insightful clues about how biology and chemistry may be thoroughly revised, referring to new models, such as informational dissipation. We trust they are enabled to address a straightforward contribution in elucidating what life is for science. This overview is not simply a philosophical speculation, but it would like to affect deeply our way to conceive and describe the foundations of organisms’ life, providing intriguing suggestions for readers in the field. Full article

Monoterpenes are plant secondary metabolites, widely used in industrial processes as precursors of important aroma compounds, such as vanillin and (−)-menthol. However, the physicochemical properties of monoterpenes make difficult their conventional conversion into value-added aromas. Biocatalysis, either by using whole cells or enzymes, may overcome such drawbacks in terms of purity of the final product, ecological and economic constraints of the current catalysis processes or extraction from plant material. In particular, the ability of oxidative enzymes (e.g., oxygenases) to modify the monoterpene backbone, with high regio- and stereo-selectivity, is attractive for the production of “natural” aromas for the flavor and fragrances industries. We review the research efforts carried out in the molecular analysis of bacterial monoterpene catabolic pathways and biochemical characterization of the respective key oxidative enzymes, with particular focus on the most relevant precursors, β-pinene, limonene and β-myrcene. The presented overview of the current state of art demonstrates that the specialized enzymatic repertoires of monoterpene-catabolizing bacteria are expanding the toolbox towards the tailored and sustainable biotechnological production of values-added aroma compounds (e.g., isonovalal, α-terpineol, and carvone isomers) whose implementation must be supported by the current advances in systems biology and metabolic engineering approaches. Full article

The term ionone is derived from “iona” (Greek for violet) which refers to the violet scent and “ketone” due to its structure. Ionones can either be chemically synthesized or endogenously produced via asymmetric cleavage of β-carotene by β-carotene oxygenase 2 (BCO2). We recently proposed a possible metabolic pathway for the conversion of α-and β-pinene into α-and β-ionone. The differences between BCO1 and BCO2 suggest a unique physiological role of BCO2; implying that β-ionone (one of BCO2 products) is involved in a prospective biological function. This review focuses on the effects of ionones and the postulated mechanisms or signaling cascades involved mediating these effects. β-Ionone, whether of an endogenous or exogenous origin possesses a range of pharmacological effects including anticancer, chemopreventive, cancer promoting, melanogenesis, anti-inflammatory and antimicrobial actions. β-Ionone mediates these effects via activation of olfactory receptor (OR51E2) and regulation of the activity or expression of cell cycle regulatory proteins, pro-apoptotic and anti-apoptotic proteins, HMG-CoA reductase and pro-inflammatory mediators. α-Ionone and β-ionone derivatives exhibit anti-inflammatory, antimicrobial and anticancer effects, however the corresponding structure activity relationships are still inconclusive. Overall, data demonstrates that ionone is a promising scaffold for cancer, inflammation and infectious disease research and thus is more than simply a violet’s fragrance. Full article

Research advances in electropolishing, with respect to the field of metalworking, have afforded significant improvements in the surface roughness and conductivity properties of aluminum polished surfaces in ways that machine polishing and simple chemical polishing cannot. The effects of a deep eutectic medium as an acid-free electrolyte were tested to determine the potential energy thresholds during electropolishing treatments based upon temperature, experiment duration, current, and voltage. Using voltammetry and chronoamperometry tests during electropolishing to supplement representative recordings via atomic force microscopy (AFM), surface morphology comparisons were performed regarding the electropolishing efficiency of phosphoric acid and acid-free ionic liquid treatments for aluminum. This eco-friendly solution produced polished surfaces superior to those surfaces treated with industry standard acid electrochemistry treatments of 1 M phosphoric acid. The roughness average of the as-received sample became 6.11 times smoother, improving from 159 nm to 26 nm when electropolished with the deep eutectic solvent. This result was accompanied by a mass loss of 0.039 g and a 7.2 µm change in step height along the edge of the electropolishing interface, whereas the acid treatment resulted in a slight improvement in surface roughness, becoming 1.63 times smoother with an average post-electropolishing roughness of 97.7 nm, yielding a mass loss of 0.0458 g and a step height of 8.1 µm. Full article