Molecules

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11 pages, 3282 KiB

Open AccessEditor’s ChoiceArticle

Efficient Hydrogen and Oxygen Evolution Catalysis Using 3D-Structured Nickel Phosphosulfide Nanosheets in Alkaline Media

by Lei Lin, Qiang Fu, Junbei Hu, Ran Wang and Xianjie Wang

Molecules 2023, 28(1), 315; https://doi.org/10.3390/molecules28010315 - 30 Dec 2022

Cited by 3 | Viewed by 2185

Abstract

Water electrolysis offers a zero-carbon route to generate renewable energy conversion systems. Herein, a self-supported nickel phosphosulfide nanosheet (NS) electrocatalyst was fabricated at a low temperature on carbon cloth, which was then subjected to Ar etching to enhance its catalytic activity. Etching resulted [...] Read more.

Water electrolysis offers a zero-carbon route to generate renewable energy conversion systems. Herein, a self-supported nickel phosphosulfide nanosheet (NS) electrocatalyst was fabricated at a low temperature on carbon cloth, which was then subjected to Ar etching to enhance its catalytic activity. Etching resulted in better hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) performance than other samples, with overpotentials of 103.1 mV (at 10 mA cm⁻²) and 278.9 mV (at 50 mA cm⁻²), respectively. The characterization results confirmed that Ar etching created a thin amorphous layer around the NiPS₃ NSs, which increased the number of active sites and modulated their electronic structures. These 3D-structured NiPS₃ NSs and their subsequent Ar etching process show promise for applications in overall water splitting in alkaline media. Full article

(This article belongs to the Special Issue Advanced Energy Storage Materials and Their Applications)

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18 pages, 13113 KiB

Open AccessEditor’s ChoiceArticle

Gaseous- and Condensed-Phase Activities of Some Reactive P- and N-Containing Fire Retardants in Polystyrenes

by Svetlana Tretsiakova-McNally, Aloshy Baby, Paul Joseph, Doris Pospiech, Eileen Schierz, Albena Lederer, Malavika Arun and Gaëlle Fontaine

Molecules 2023, 28(1), 278; https://doi.org/10.3390/molecules28010278 - 29 Dec 2022

Cited by 2 | Viewed by 1956

Abstract

Polystyrene (PS) was modified by covalently binding P-, P-N- and/or N- containing fire-retardant moieties through co- or ter-polymerization reactions of styrene with diethyl(acryloyloxymethyl)phosphonate (DEAMP), diethyl-p-vinylbenzyl phosphonate (DEpVBP), acrylic acid-2-[(diethoxyphosphoryl)methylamino]ethyl ester (ADEPMAE) and maleimide (MI). In the present study, the condensed-phase and [...] Read more.

Polystyrene (PS) was modified by covalently binding P-, P-N- and/or N- containing fire-retardant moieties through co- or ter-polymerization reactions of styrene with diethyl(acryloyloxymethyl)phosphonate (DEAMP), diethyl-p-vinylbenzyl phosphonate (DEpVBP), acrylic acid-2-[(diethoxyphosphoryl)methylamino]ethyl ester (ADEPMAE) and maleimide (MI). In the present study, the condensed-phase and the gaseous-phase activities of the abovementioned fire retardants within the prepared co- and ter-polymers were evaluated for the first time. Pyrolysis–Gas Chromatography/Mass Spectrometry was employed to identify the volatile products formed during the thermal decomposition of the modified polymers. Benzaldehyde, α-methylstyrene, acetophenone, triethyl phosphate and styrene (monomer, dimer and trimer) were detected in the gaseous phase following the thermal cracking of fire-retardant groups and through main chain scissions. In the case of PS modified with ADEPMAE, the evolution of pyrolysis gases was suppressed by possible inhibitory actions of triethyl phosphate in the gaseous phase. The reactive modification of PS by simultaneously incorporating P- (DEAMP or DEpVBP) and N- (MI) monomeric units, in the chains of ter-polymers, resulted in a predominantly condensed-phase mode of action owing to synergistic P and N interactions. The solid-state ³¹P NMR spectroscopy, Scanning Electron Microscopy/Energy Dispersive Spectroscopy, Inductively-Coupled Plasma/Optical Emission Spectroscopy and X-ray Photoelectron Spectroscopy of char residues, obtained from ter-polymers, confirmed the retention of the phosphorus species in their structures. Full article

(This article belongs to the Special Issue Feature Papers in Materials Chemistry)

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12 pages, 6615 KiB

Open AccessEditor’s ChoiceArticle

Low-Temperature Toluene Oxidation on Fe-Containing Modified SBA-15 Materials

by Ivalina Trendafilova, Manuel Ojeda, John M. Andresen, Alenka Ristić, Momtchil Dimitrov, Nataša Novak Tušar, Genoveva Atanasova and Margarita Popova

Molecules 2023, 28(1), 204; https://doi.org/10.3390/molecules28010204 - 26 Dec 2022

Cited by 2 | Viewed by 1935

Abstract

Transition metals as catalysts for total VOC oxidation at low temperatures (150–280 °C) are a big challenge nowadays. Therefore, iron-modified SBA-15, AlSBA-15, and ZrSBA-15 materials with 0.5 to 5.0 wt.% Fe loading were prepared and tested for toluene oxidation. It was found that [...] Read more.

Transition metals as catalysts for total VOC oxidation at low temperatures (150–280 °C) are a big challenge nowadays. Therefore, iron-modified SBA-15, AlSBA-15, and ZrSBA-15 materials with 0.5 to 5.0 wt.% Fe loading were prepared and tested for toluene oxidation. It was found that increasing Fe loading significantly improved the rate of oxidation and lowered the temperature of achieving 100% removal of toluene from above 500 °C for the supports (AlSBA-15 and ZrSBA-15) to below 400 °C for 5FeZrSBA-15. The formation of finely dispersed iron oxide active sites with a particle size less than 5 nm was observed on all the SBA-15, AlSBA-15, and ZrSBA-15 supports. It was found that the surface properties of the mesoporous support due to the addition of Al or Zr predetermined the type of formed iron oxide species and their localization on the support surface. Fe-containing SBA-15 and AlSBA-15 showed activity in total toluene oxidation at higher temperatures (280–450 °C). However, 5 wt. % Fe-containing ZrSBA-15 showed excellent activity in the total oxidation of toluene as a model VOC at lower temperatures (150–380 °C) due to the synergistic effect of Fe-Zr and the presence of accessible and stable Fe²⁺/Fe³⁺ active sites. Full article

(This article belongs to the Special Issue Catalysis by Hybrid Materials)

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14 pages, 1133 KiB

Open AccessEditor’s ChoiceArticle

Possibility of New Active Substrates (ASs) to Be Used to Prevent the Migration of Heavy Metals to the Soil and Water Environments

by Katarzyna Witt, Waldemar Studziński and Daria Bożejewicz

Molecules 2023, 28(1), 94; https://doi.org/10.3390/molecules28010094 - 22 Dec 2022

Viewed by 1391

Abstract

This paper aims to propose an alternative to the known permeable reactive barriers (PRBs). PRB is one of the methods, which is a reactive barrier placed below the ground, to clean up contaminated groundwater. New polymer active substrates (ASs) were used to prevent [...] Read more.

This paper aims to propose an alternative to the known permeable reactive barriers (PRBs). PRB is one of the methods, which is a reactive barrier placed below the ground, to clean up contaminated groundwater. New polymer active substrates (ASs) were used to prevent soil contamination by toxic heavy metals. The active substrates consisted of a mixture of poly(vinyl chloride), Aliquat 336, and bis(2-ethylhexyl)adipate, which was applied to the skeleton material (fiberglass or textile). Aliquat 336 was used as a binding agent for metal ions (Cr(VI), Ni(II), Cu(II), Zn(II), Cd(II), and Pb(II)). In contrast with the PRBs, the ASs (from AS-1 to AS-5) were obtained in a simple way using the pouring method. The obtained ASs could be recycled and reused. The active substrates were used for the binding of various metal ions from aqueous solutions and the examined soil. It was found that the active substrate AS-1 decreased the concentrations of nickel, cadmium, and lead by more than 50% and that of chromium by more than 90% in the aqueous solution. High sorption efficiency for chromium and zinc metals (81% and 66%) with the use of AS-2 was also found, owing to which the migration of metals from soil to water can be limited. In the soil environment, active substrate AS-5 with the addition of a plasticizer showed the greatest effectiveness. This solution resulted in a reduction in each tested metal ion of at least 50%, and reductions in cadmium, lead, and copper of over 70%. Full article

(This article belongs to the Special Issue Innovative Adsorbents for Water Treatment)

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15 pages, 3575 KiB

Open AccessEditor’s ChoiceArticle

Electrochemical Characterization and Voltammetric Determination of Methylisothiazolinone on a Boron-Doped Diamond Electrode

by Magdalena Jakubczyk, Slawomir Michalkiewicz, Agata Skorupa and Kinga Krajcarz

Molecules 2022, 27(24), 9013; https://doi.org/10.3390/molecules27249013 - 17 Dec 2022

Viewed by 1840

Abstract

The electrochemical properties of methylisothiazolinone (MIT), the most widely used preservative, were investigated by cyclic (CV) and differential pulse voltammetry (DPV) to develop a new method for its determination. To our knowledge, this is the first demonstration of a voltammetric procedure for the [...] Read more.

The electrochemical properties of methylisothiazolinone (MIT), the most widely used preservative, were investigated by cyclic (CV) and differential pulse voltammetry (DPV) to develop a new method for its determination. To our knowledge, this is the first demonstration of a voltammetric procedure for the determination of MIT on a boron-doped diamond electrode (BDDE) in a citrate–phosphate buffer (C-PB) environment. The anodic oxidation process of methylisothiazolinone, which is the basis of this method, proved to be diffusion-controlled and proceeded with an irreversible two-electron exchange. The radical cations, as unstable primary products, were converted in subsequent chemical reactions to sulfoxides and sulfones, and finally to more stable final products. Performed determinations were based on the DPV technique. A linear calibration curve was obtained in the concentration range from 0.7 to 18.7 mg L⁻¹, with a correlation coefficient of 0.9999. The proposed procedure was accurate and precise, allowing the detection of MIT at a concentration level of 0.24 mg L⁻¹. It successfully demonstrated its suitability for the determination of methylisothiazolinone in household products without the need for any separation steps. The proposed method can serve as an alternative to the prevailing chromatographic determinations of MIT in real samples. Full article

(This article belongs to the Special Issue New Science of Boron Allotropes, Compounds, and Nanomaterials)

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14 pages, 4814 KiB

Open AccessEditor’s ChoiceArticle

Desorption of Ammonia Adsorbed on Prussian Blue Analogs by Washing with Saturated Ammonium Hydrogen Carbonate Solution

by Hatsuho Usuda, Yoshie Mishima, Tohru Kawamoto and Kimitaka Minami

Molecules 2022, 27(24), 8840; https://doi.org/10.3390/molecules27248840 - 13 Dec 2022

Cited by 2 | Viewed by 2330

Abstract

Prussian blue analogs (PBAs) have been reported as promising ammonia (NH₃) adsorbents with a high capacity compared to activated carbon, zeolite, and ion exchange resins. The adsorbed NH₃ was desorbed by heating and washing with water or acid. Recently, we [...] Read more.

Prussian blue analogs (PBAs) have been reported as promising ammonia (NH₃) adsorbents with a high capacity compared to activated carbon, zeolite, and ion exchange resins. The adsorbed NH₃ was desorbed by heating and washing with water or acid. Recently, we demonstrated that desorption was also possible by washing with a saturated ammonium hydrogen carbonate solution (sat. NH₄HCO₃aq) and recovered NH₃ as an NH₄HCO₃ solid by introducing CO₂ into the washing liquid after desorption. However, this has only been proven for copper ferrocyanide and the relationship between the adsorption/desorption behavior and metal ions in PBAs has not been identified. In this study, we investigated the adsorption/desorption behavior of PBAs that are complexes of first row transition metals with hexacyanometalate anions. Six types of PBAs were tested in this study and copper ferricyanide exhibited the highest desorption/adsorption ratio. X-ray diffraction results revealed high structural stability for cobalt hexacyanocobaltate (CoHCC) and nickel ferricyanide (NiHCF). The Fourier transform infrared spectroscopy results showed that the NH₃ adsorbed on the vacancy sites tended to desorb compared to the NH₃ adsorbed on the interstitial sites as ammonium ions. Interestingly, the desorption/adsorption ratio exhibited the Irving-Williams order. Full article

(This article belongs to the Special Issue Feature Papers in Materials Chemistry)

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27 pages, 5817 KiB

Open AccessEditor’s ChoiceArticle

The Effect of Combined Atmospheric Plasma/UV Treatments on Improving the Durability of Flame Retardants Applied to Cotton

by Maram Ayesh, Arthur Richard Horrocks and Baljinder K. Kandola

Molecules 2022, 27(24), 8737; https://doi.org/10.3390/molecules27248737 - 9 Dec 2022

Cited by 4 | Viewed by 1610

Abstract

Application of a combined atmospheric plasma/UV laser to cotton fabrics impregnated with selected non-durable flame retardants (FRs) has shown evidence of covalent grafting of the latter species on to cotton fibre surfaces. As a result, an increase in their durability to water-soaking for [...] Read more.

Application of a combined atmospheric plasma/UV laser to cotton fabrics impregnated with selected non-durable flame retardants (FRs) has shown evidence of covalent grafting of the latter species on to cotton fibre surfaces. As a result, an increase in their durability to water-soaking for 30 min at 40 °C has been recorded. Based on previous research plasma gases comprising Ar^80%/CO₂^20% or N₂^80%/O₂^20% were used to pre-expose cotton fabric prior to or after FR impregnation to promote the formation of radical species and increased –COOH groups on surface cellulosic chains, which would encourage formation of FR-cellulose bonds. Analysis by scanning electron microscopy (SEM/EDX), X-ray photoelectron spectroscopy (XPS) and thermal analysis (TGA) suggested that organophosphorus- and nitrogen- containing flame retarding species in the presence of the silicon-containing molecules such as 3-aminopropyltriethoxy silane (APTS) resulted in formation of FR-S-O-cellulose links, which gave rise to post-water-soaking FR retentions > 10%. Similarly, the organophosphorus FR, diethyl N, N bis (2-hydroxyethyl) aminomethylphosphonate (DBAP), after plasma/UV exposure produced similar percentage retention values possibly via (PO).O.cellulose bond formation, While none of the plasmas/UV-treated, FR-impregnated fabrics showed self-extinction behaviour, although burning rates reduced and significant char formation was evident, it has been shown that FR durability may be increased using plasma/UV treatments. Full article

(This article belongs to the Special Issue Flame-Resistant Materials)

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16 pages, 2368 KiB

Open AccessEditor’s ChoiceArticle

Direct Correlation of Surface Tension and Surface Composition of Ionic Liquid Mixtures—A Combined Vacuum Pendant Drop and Angle-Resolved X-ray Photoelectron Spectroscopy Study

by Ulrike Paap, Vera Seidl, Karsten Meyer, Florian Maier and Hans-Peter Steinrück

Molecules 2022, 27(23), 8561; https://doi.org/10.3390/molecules27238561 - 5 Dec 2022

Cited by 6 | Viewed by 1567

Abstract

We investigated the surface tension and surface composition of various mixtures of the two ionic liquids (ILs) 1-methyl-3-octyl-imidazolium hexafluorophosphate [C₈C₁Im][PF₆] and 1,3-bis(polyethylene glycol)imidazolium iodide [(mPEG₂)₂Im]I in the temperature range from 230 [...] Read more.

We investigated the surface tension and surface composition of various mixtures of the two ionic liquids (ILs) 1-methyl-3-octyl-imidazolium hexafluorophosphate [C₈C₁Im][PF₆] and 1,3-bis(polyethylene glycol)imidazolium iodide [(mPEG₂)₂Im]I in the temperature range from 230 to 370 K under ultraclean vacuum conditions. The surface tension was measured using a newly developed apparatus, and the surface composition was determined by angle-resolved X-ray photoelectron spectroscopy (ARXPS). In the pure ILs, the alkyl chains of [C₈C₁Im][PF₆] and the PEG chains of [(mPEG₂)₂Im]I are enriched at the IL/vacuum interface. In the mixtures, a strong selective surface enrichment of the alkyl chains occurs, which is most pronounced at low [C₈C₁Im][PF₆] contents. For the surface tension, strong deviations from an ideal mixing behaviour take place. By applying a simple approach based on the surface composition of the mixtures as deduced from ARXPS, we are able to predict and reproduce the experimentally measured temperature-dependent surface tension values with astonishingly high accuracy. Full article

(This article belongs to the Special Issue Properties and Applications of Ionic Liquids-Based Advanced Materials)

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17 pages, 2840 KiB

Open AccessEditor’s ChoiceArticle

The Chemistry of Phenylimidotechnetium(V) Complexes with Isocyanides: Steric and Electronic Factors

by Guilhem Claude, Laura Zeh, Maximilian Roca Jungfer, Adelheid Hagenbach, Joshua S. Figueroa and Ulrich Abram

Molecules 2022, 27(23), 8546; https://doi.org/10.3390/molecules27238546 - 4 Dec 2022

Cited by 5 | Viewed by 22381

Abstract

Organometallic approaches are of ongoing interest for the development of novel functional ^99mTc radiopharmaceuticals, while the basic organotechnetium chemistry seems frequently to be little explored. Thus, structural and reactivity studies with the long-lived isotope ⁹⁹Tc are of permanent interest as the [...] Read more.

Organometallic approaches are of ongoing interest for the development of novel functional ^99mTc radiopharmaceuticals, while the basic organotechnetium chemistry seems frequently to be little explored. Thus, structural and reactivity studies with the long-lived isotope ⁹⁹Tc are of permanent interest as the foundation for further progress in the related radiopharmaceutical research with this artificial element. Particularly the knowledge about the organometallic chemistry of high-valent technetium compounds is scarcely developed. Here, phenylimido complexes of technetium(V) with different isocyanides are introduced. They have been synthesized by ligand-exchange procedures starting from [Tc(NPh)Cl₃(PPh₃)₂]. Different reactivity patterns and products have been obtained depending on the steric and electronic properties of the individual ligands. This involves the formation of 1:1 and 1:2 exchange products of Tc(V) with the general formulae [Tc(NPh)Cl₃(PPh₃)(isocyanide)], cis- or trans-[Tc(NPh)Cl₃(isocyanide)₂], but also the reduction in the metal and the formation of cationic technetium(I) complex of the formula [Tc(isocyanide)₆]⁺ when p-fluorophenyl isocyanide is used. The products have been studied by single-crystal X-ray diffraction and spectroscopic methods, including IR and multinuclear NMR spectroscopy. DFT calculations on the different isocyanides allow the prediction of their reactivity towards electron-rich and electron-deficient metal centers by means of the empirical SADAP parameter, which has been derived from the potential energy surface of the electron density on their potentially coordinating carbon atoms. Full article

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

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12 pages, 4011 KiB

Open AccessEditor’s ChoiceArticle

Toward High-Performance Electrochromic Conjugated Polymers: Influence of Local Chemical Environment and Side-Chain Engineering

by Kaiwen Lin, Changjun Wu, Guangyao Zhang, Zhixin Wu, Shiting Tang, Yingxin Lin, Xinye Li, Yuying Jiang, Hengjia Lin, Yuehui Wang, Shouli Ming and Baoyang Lu

Molecules 2022, 27(23), 8424; https://doi.org/10.3390/molecules27238424 - 1 Dec 2022

Cited by 13 | Viewed by 1482

Abstract

Three homologous electrochromic conjugated polymers, each containing an asymmetric building block but decorated with distinct alkyl chains, were designed and synthesized using electrochemical polymerization in this study. The corresponding monomers, namely T610FBTT810, DT6FBT, and DT48FBT, comprise the same backbone structure, i.e., an asymmetric [...] Read more.

Three homologous electrochromic conjugated polymers, each containing an asymmetric building block but decorated with distinct alkyl chains, were designed and synthesized using electrochemical polymerization in this study. The corresponding monomers, namely T610FBTT810, DT6FBT, and DT48FBT, comprise the same backbone structure, i.e., an asymmetric 5-fluorobenzo[c][1,2,5]thiadiazole unit substituted by two thiophene terminals, but were decorated with different types of alkyl chain (hexyl, 2-butyloctyl, 2-hexyldecyl, or 2-octyldecyl). The effects of the side-chain structure and asymmetric repeating unit on the optical absorption, electrochemistry, morphology, and electrochromic properties were investigated comparatively. It was found that the electrochromism conjugated polymer, originating from DT6FBT with the shortest and linear alkyl chain, exhibits the best electrochromic performance with a 25% optical contrast ratio and a 0.3 s response time. The flexible electrochromic device of PDT6FBT achieved reversible colors of navy and cyan between the neutral and oxidized states, consistent with the non-device phenomenon. These results demonstrate that subtle modification of the side chain is able to change the electrochromic properties of conjugated polymers. Full article

(This article belongs to the Special Issue Structure and Electronic Properties of Conjugated Polymers and Nanocomposites)

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21 pages, 6322 KiB

Open AccessEditor’s ChoiceArticle

Selective Oxidation of Glycerol via Acceptorless Dehydrogenation Driven by Ir(I)-NHC Catalysts

by M. Victoria Jiménez, Ana I. Ojeda-Amador, Raquel Puerta-Oteo, Joaquín Martínez-Sal, Vincenzo Passarelli and Jesús J. Pérez-Torrente

Molecules 2022, 27(22), 7666; https://doi.org/10.3390/molecules27227666 - 8 Nov 2022

Cited by 2 | Viewed by 1938

Abstract

Iridium(I) compounds featuring bridge-functionalized bis-NHC ligands (NHC = N-heterocyclic carbene), [Ir(cod)(bis-NHC)] and [Ir(CO)₂(bis-NHC)], have been prepared from the appropriate carboxylate- or hydroxy-functionalized bis-imidazolium salts. The related complexes [Ir(cod)(NHC)₂]⁺ and [IrCl(cod)(NHC)(cod)] have been synthesized from a 3-hydroxypropyl functionalized imidazolium [...] Read more.

Iridium(I) compounds featuring bridge-functionalized bis-NHC ligands (NHC = N-heterocyclic carbene), [Ir(cod)(bis-NHC)] and [Ir(CO)₂(bis-NHC)], have been prepared from the appropriate carboxylate- or hydroxy-functionalized bis-imidazolium salts. The related complexes [Ir(cod)(NHC)₂]⁺ and [IrCl(cod)(NHC)(cod)] have been synthesized from a 3-hydroxypropyl functionalized imidazolium salt. These complexes have been shown to be robust catalysts in the oxidative dehydrogenation of glycerol to lactate (LA) with dihydrogen release. High activity and selectivity to LA were achieved in an open system under low catalyst loadings using KOH as a base. The hydroxy-functionalized bis-NHC catalysts are much more active than both the carboxylate-functionalized ones and the unbridged bis-NHC iridium(I) catalyst with hydroxyalkyl-functionalized NHC ligands. In general, carbonyl complexes are more active than the related 1,5-cyclooctadiene ones. The catalyst [Ir(CO)₂{(MeImCH₂)₂CHOH}]Br exhibits the highest productivity affording TONs to LA up to 15,000 at very low catalyst loadings. Full article

(This article belongs to the Special Issue Synthesis, Characterization, and Catalytic Activity of Organometallic Complexes 2022)

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20 pages, 6561 KiB

Open AccessEditor’s ChoiceArticle

Molecular Engineering of Quinone-Based Nickel Complexes and Polymers for All-Organic Li-Ion Batteries

by Yanislav Danchovski, Hristo Rasheev, Radostina Stoyanova and Alia Tadjer

Molecules 2022, 27(20), 6805; https://doi.org/10.3390/molecules27206805 - 11 Oct 2022

Cited by 2 | Viewed by 1779

Abstract

All-organic Li-ion batteries appear to be a sustainable and safer alternative to the currently-used Li-ion batteries but their application is still limited due to the lack of organic compounds with high redox potentials toward Li⁺/Li⁰. Herein, we report a [...] Read more.

All-organic Li-ion batteries appear to be a sustainable and safer alternative to the currently-used Li-ion batteries but their application is still limited due to the lack of organic compounds with high redox potentials toward Li⁺/Li⁰. Herein, we report a computational design of nickel complexes and coordination polymers that have redox potentials spanning the full voltage range: from the highest, 4.7 V, to the lowest, 0.4 V. The complexes and polymers are modeled by binding low- and high-oxidized Ni ions (i.e., Ni(II) and Ni(IV)) to redox-active para-benzoquinone molecules substituted with carboxyl- and cyano-groups. It is found that both the nickel ions and the quinone-derived ligands are redox-active upon lithiation. The type of Ni coordination also has a bearing on the redox potentials. By combining the complex of Ni(IV) with 2-carboxylato-5-cyano-1,4-benzoquinones as a cathode and Ni(II)-2,5-dicarboxylato-3,6-dicyano-1,4-benzoquinone coordination polymer as an anode, all-organic Li-ion batteries could be assembled, operating at an average voltage exceeding 3.0 V and delivering a capacity of more than 300 mAh/g. Full article

(This article belongs to the Special Issue Metal-Organic Complexes: Applications in Chemistry and Materials Science)

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29 pages, 9817 KiB

Open AccessEditor’s ChoiceArticle

A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

by Dana R. Chambers, Agnieszka Sulima, Dan Luo, Thomas E. Prisinzano, Alexander Goldberg, Bing Xie, Lei Shi, Carol A. Paronis, Jack Bergman, Nima Nassehi, Dana E. Selley, Gregory H. Imler, Arthur E. Jacobson and Kenner C. Rice

Molecules 2022, 27(19), 6455; https://doi.org/10.3390/molecules27196455 - 30 Sep 2022

Cited by 6 | Viewed by 1960

Abstract

Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in [...] Read more.

Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [³⁵S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences. Full article

(This article belongs to the Section Medicinal Chemistry)

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19 pages, 7069 KiB

Open AccessEditor’s ChoiceArticle

Detailed Structural Characterization of Oxidized Sucrose and Its Application in the Fully Carbohydrate-Based Preparation of a Hydrogel from Carboxymethyl Chitosan

by Hiroyuki Kono, Junki Noda and Haruki Wakamori

Molecules 2022, 27(18), 6137; https://doi.org/10.3390/molecules27186137 - 19 Sep 2022

Cited by 6 | Viewed by 2368

Abstract

Oxidized sucrose (OS) is a bio-based cross-linking agent with excellent biological safety and environmental non-toxicity. However, the precise structure of OS has not been elucidated owing to its structural complexity and low purity. Accordingly, in this study, complete chemical shift assignments were performed [...] Read more.

Oxidized sucrose (OS) is a bio-based cross-linking agent with excellent biological safety and environmental non-toxicity. However, the precise structure of OS has not been elucidated owing to its structural complexity and low purity. Accordingly, in this study, complete chemical shift assignments were performed by applying various nuclear magnetic resonance techniques, which permitted the structural and quantitative characterization of the two main OS products, each of which contained four aldehyde groups. In addition, we investigated the use of OS as a cross-linking agent in the preparation of a hydrogel from carboxymethyl chitosan (CMC), one of the most popular polysaccharides for use in biomedical applications. The primary amine groups of CMC were immediately cross-linked with the aldehyde groups of OS to form hydrogels without the requirement for a catalyst. It was found that the degree of cross-linking could be easily controlled by the feed amount of OS during CMC hydrogel preparation and the final cross-linking degree affected the thermal, swelling, and rheological properties of the obtained hydrogel. The results presented in this study are therefore expected to be applicable in the preparation of fully carbohydrate-based hydrogels for medical and pharmaceutical applications. Full article

(This article belongs to the Section Macromolecular Chemistry)

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11 pages, 2175 KiB

Open AccessEditor’s ChoiceArticle

Customizing Pore System in a Microporous Metal–Organic Framework for Efficient C₂H₂ Separation from CO₂ and C₂H₄

by Qiang Zhang, Guan-Nan Han, Xin Lian, Shan-Qing Yang and Tong-Liang Hu

Molecules 2022, 27(18), 5929; https://doi.org/10.3390/molecules27185929 - 12 Sep 2022

Cited by 4 | Viewed by 4148

Abstract

Selective-adsorption separation is an energy-efficient technology for the capture of acetylene (C₂H₂) from carbon dioxide (CO₂) and ethylene (C₂H₄). However, it remains a critical challenge to effectively recognize C₂H₂ among [...] Read more.

Selective-adsorption separation is an energy-efficient technology for the capture of acetylene (C₂H₂) from carbon dioxide (CO₂) and ethylene (C₂H₄). However, it remains a critical challenge to effectively recognize C₂H₂ among CO₂ and C₂H₄, owing to their analogous molecule sizes and physical properties. Herein, we report a new microporous metal–organic framework (NUM-14) possessing a carefully tailored pore system containing moderate pore size and nitro-functionalized channel surface for efficient separation of C₂H₂ from CO₂ and C₂H₄. The activated NUM-14 (namely NUM-14a) exhibits sufficient pore space to acquire excellent C₂H₂ loading capacity (4.44 mmol g⁻¹) under ambient conditions. In addition, it possesses dense nitro groups, acting as hydrogen bond acceptors, to selectively identify C₂H₂ molecules rather than CO₂ and C₂H₄. The breakthrough experiments demonstrate the good actual separation ability of NUM-14a for C₂H₂/CO₂ and C₂H₂/C₂H₄ mixtures. Furthermore, Grand Canonical Monte Carlo simulations indicate that the pore surface of the NUM-14a has a stronger affinity to preferentially bind C₂H₂ over CO₂ and C₂H₄ via stronger C-H···O hydrogen bond interactions. This article provides some insights into customizing pore systems with desirable pore sizes and modifying groups in terms of MOF materials toward the capture of C₂H₂ from CO₂ and C₂H₄ to promote the development of more MOF materials with excellent properties for gas adsorption and separation. Full article

(This article belongs to the Special Issue Advanced Crystalline Porous Material and Engineering for Separation and Catalysis Application)

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20 pages, 2079 KiB

Open AccessEditor’s ChoiceArticle

Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin

by Mirosława Grymel, Anna Lalik, Alicja Kazek-Kęsik, Marietta Szewczyk, Patrycja Grabiec and Karol Erfurt

Molecules 2022, 27(16), 5156; https://doi.org/10.3390/molecules27165156 - 12 Aug 2022

Cited by 10 | Viewed by 1809

Abstract

For several decades, natural products have been widely researched and their native scaffolds are the basis for the design and synthesis of new potential therapeutic agents. Betulin is an interesting biologically attractive natural parent molecule with a high safety profile and can easily [...] Read more.

For several decades, natural products have been widely researched and their native scaffolds are the basis for the design and synthesis of new potential therapeutic agents. Betulin is an interesting biologically attractive natural parent molecule with a high safety profile and can easily undergo a variety of structural modifications. Herein, we describe the synthesis of new molecular hybrids of betulin via covalent linkage with an alkyltriphenylphosphonium moiety. The proposed strategy enables the preparation of semi-synthetic derivatives (28-TPP^⊕ BN and 3,28-bisTPP^⊕ BN) from betulin through simple transformations in high yields. The obtained results showed that the presence of a lipophilic cation improved the solubility of the tested analogs compared to betulin, and increased their cytotoxicity. Among the triphenylphosphonium derivatives tested, analogs 7a (IC₅₀ of 5.56 µM) and 7b (IC₅₀ of 5.77 µM) demonstrated the highest cytotoxicity against the colorectal carcinoma cell line (HCT 116). TPP^⊕-conjugates with betulin showed antimicrobial properties against Gram-positive reference Staphylococcus aureus ATCC 25923 and Staphylococcus epidermidis ATCC 12228 bacteria, at a 200 µM concentration in water. Hence, the conjugation of betulin’s parent backbone with a triphenylphosphonium moiety promotes transport through the hydrophobic barriers of the mitochondrial membrane, making it a promising strategy to improve the bioavailability of natural substances. Full article

(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)

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22 pages, 5227 KiB

Open AccessEditor’s ChoiceArticle

Supramolecular cis-“Bis(Chelation)” of [M(CN)₆]³⁻ (M = Cr^III, Fe^III, Co^III) by Phloroglucinol (H₃PG)

by Katarzyna Jędrzejowska, Jedrzej Kobylarczyk, Dorota Glosz, Emilia Kuzniak-Glanowska, Dominika Tabor, Monika Srebro-Hooper, Jakub J. Zakrzewski, Katarzyna Dziedzic-Kocurek, Tadeusz M. Muzioł and Robert Podgajny

Molecules 2022, 27(13), 4111; https://doi.org/10.3390/molecules27134111 - 26 Jun 2022

Cited by 2 | Viewed by 4482

Abstract

Studies on molecular co-crystal type materials are important in the design and preparation of easy-to-absorb drugs, non-centrosymmetric, and chiral crystals for optical performance, liquid crystals, or plastic phases. From a fundamental point of view, such studies also provide useful information on various supramolecular [...] Read more.

Studies on molecular co-crystal type materials are important in the design and preparation of easy-to-absorb drugs, non-centrosymmetric, and chiral crystals for optical performance, liquid crystals, or plastic phases. From a fundamental point of view, such studies also provide useful information on various supramolecular synthons and molecular ordering, including metric parameters, molecular matching, energetical hierarchy, and combinatorial potential, appealing to the rational design of functional materials through structure–properties–application schemes. Co-crystal salts involving anionic d-metallate coordination complexes are moderately explored (compared to the generality of co-crystals), and in this context, we present a new series of isomorphous co-crystalline salts (PPh₄)₃[M(CN)₆](H₃PG)₂·2MeCN (M = Cr, 1; Fe, 2; Co 3; H₃PG = phloroglucinol, 1,3,5-trihydroxobenzene). In this study, 1–3 were characterized experimentally using SC XRD, Hirshfeld analysis, ESI-MS spectrometry, vibrational IR and Raman, ⁵⁷Fe Mössbauer, electronic absorption UV-Vis-NIR, and photoluminescence spectroscopies, and theoretically with density functional theory calculations. The two-dimensional square grid-like hydrogen-bond {[M(CN)₆]³⁻;(H₃PG)₂}_∞ network features original {[M(CN)₆]³⁻;(H₃PG)₄} supramolecular cis-bis(chelate) motifs involving: (i) two double cyclic hydrogen bond synthons M(-CN⋅⋅⋅HO-)₂Ar, {[M(CN)₆]³⁻;H₂PGH}, between cis-oriented cyanido ligands of [M(CN)₆]³⁻ and resorcinol-like face of H₃PG, and (ii) two single hydrogen bonds M-CN⋅⋅⋅HO-Ar, {[M(CN)₆]³⁻;HPGH₂}, involving the remaining two cyanide ligands. The occurrence of the above tectonic motif is discussed with regard to the relevant data existing in the CCDC database, including the multisite H-bond binding of [M(CN)₆]³⁻ by organic species, mononuclear coordination complexes, and polynuclear complexes. The physicochemical and computational characterization discloses notable spectral modifications under the regime of an extended hydrogen bond network. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Inorganic Chemistry Section of Molecules)

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16 pages, 3389 KiB

Open AccessEditor’s ChoiceArticle

Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain

by Lisa L. Wilson, Amy R. Alleyne, Shainnel O. Eans, Thomas J. Cirino, Heather M. Stacy, Marco Mottinelli, Sebastiano Intagliata, Christopher R. McCurdy and Jay P. McLaughlin

Molecules 2022, 27(11), 3617; https://doi.org/10.3390/molecules27113617 - 4 Jun 2022

Cited by 12 | Viewed by 2625

Abstract

Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities [...] Read more.

Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities of a novel S2R selective ligand, 1-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-3-methyl-1,3-dihydro-1,3-benzimidazol-2-one (CM-398). The inhibition of thermal, induced chemical, or inflammatory pain as well as the allodynia resulting from chronic nerve constriction injury (CCI) model of neuropathic pain were assessed in male mice. CM-398 dose-dependently (10–45 mg/kg i.p.) reduced mechanical allodynia in the CCI neuropathic pain model, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg i.p.). Likewise, pretreatment (i.p.) with CM-398 dose-dependently produced antinociception in the acetic acid writhing test (ED₅₀ (and 95% C.I.) = 14.7 (10.6–20) mg/kg, i.p.) and the formalin assay (ED₅₀ (and 95% C.I.) = 0.86 (0.44–1.81) mg/kg, i.p.) but was without effect in the 55 °C warm-water tail-withdrawal assay. A high dose of CM-398 (45 mg/kg, i.p.) exhibited modest locomotor impairment in a rotarod assay and conditioned place aversion, potentially complicating the interpretation of nociceptive testing. However, in an operant pain model resistant to these confounds, mice experiencing CCI and treated with CM-398 demonstrated robust conditioned place preference. Overall, these results demonstrate the S2R selective antagonist CM-398 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, adding to emerging data suggesting possible mediation of nociception by S2R, and the development of S2R ligands as potential treatments for chronic pain. Full article

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

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15 pages, 3240 KiB

Open AccessEditor’s ChoiceArticle

Synthesis, Crystal Structure and Magnetic Properties of a Trinuclear Copper(II) Complex Based on P-Cresol-Substituted Bis(α-Nitronyl Nitroxide) Biradical

by Sabrina Grenda, Maxime Beau and Dominique Luneau

Molecules 2022, 27(10), 3218; https://doi.org/10.3390/molecules27103218 - 18 May 2022

Cited by 1 | Viewed by 2414

Abstract

Trinuclear copper(II) complex [Cu^II₃(NIT₂PhO)₂Cl₄] was synthesized with p-cresol-substituted bis(α-nitronyl nitroxide) biradical: 4-methyl-2,6-bis(1-oxyl-3-oxido-4,4,5,5-tetramethyl-2-imidazolin-2-yl)phenol (NIT₂PhOH). The crystal structure of this heterospin complex was determined using single-crystal X-ray diffraction analysis and exhibits four unusual seven-membered [...] Read more.

Trinuclear copper(II) complex [Cu^II₃(NIT₂PhO)₂Cl₄] was synthesized with p-cresol-substituted bis(α-nitronyl nitroxide) biradical: 4-methyl-2,6-bis(1-oxyl-3-oxido-4,4,5,5-tetramethyl-2-imidazolin-2-yl)phenol (NIT₂PhOH). The crystal structure of this heterospin complex was determined using single-crystal X-ray diffraction analysis and exhibits four unusual seven-membered metallocycles formed from the coordination of oxygen atoms of the N-O groups and of bridging phenoxo (µ-PhO⁻) moieties with copper(II) ions. The crystal structure analysis reveals an incipient agostic interaction between a square planar copper center and a hydrogen-carbon bond from one methyl group carried on the coordinated nitronyl-nitroxide radical. The intramolecular Cu∙∙∙H-C interaction involves a six-membered metallocycle and may stabilize the copper center in square planar coordination mode. From the magnetic susceptibility measurements, the complex, which totals seven S = 1/2 spin carriers, has almost a ground state spin S = 1/2 at room temperature ascribed to strong antiferromagnetic interaction between the nitronyl nitroxide moieties and the copper(II) centers and in between the copper(II) centers through the bridging phenoxo oxygen atom. Full article

(This article belongs to the Special Issue Crystal Structures of Metal Complexes)

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13 pages, 2073 KiB

Open AccessEditor’s ChoiceArticle

Conditions to Control Furan Ring Opening during Furfuryl Alcohol Polymerization

by Lucie Quinquet, Pierre Delliere and Nathanael Guigo

Molecules 2022, 27(10), 3212; https://doi.org/10.3390/molecules27103212 - 17 May 2022

Cited by 11 | Viewed by 2948

Abstract

The chemistry of biomass-derived furans is particularly sensitive to ring openings. These side reactions occur during furfuryl alcohol polymerization. In this work, the furan ring-opening was controlled by changing polymerization conditions, such as varying the type of acidic initiator or the water content. [...] Read more.

The chemistry of biomass-derived furans is particularly sensitive to ring openings. These side reactions occur during furfuryl alcohol polymerization. In this work, the furan ring-opening was controlled by changing polymerization conditions, such as varying the type of acidic initiator or the water content. The degree of open structures (DOS) was determined by quantifying the formed carbonyl species by means of quantitative ¹⁹F NMR and potentiometric titration. The progress of polymerization and ring opening were monitored by DSC and FT-IR spectroscopy. The presence of additional water is more determining on ring opening than the nature of the acidic initiator. Qualitative structural assessment by means of ¹³C NMR and FT-IR shows that, depending on the employed conditions, poly(furfuryl alcohol) samples can be classified in two groups. Indeed, either more ester or more ketone side groups are formed as a result of side ring opening reactions. The absence of additional water during FA polymerization preferentially leads to opened structures in the PFA bearing more ester moieties. Full article

(This article belongs to the Special Issue Natural Polymers and Biopolymers III)

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26 pages, 6258 KiB

Open AccessEditor’s ChoiceArticle

Affinity Proteomics Identifies Interaction Partners and Defines Novel Insights into the Function of the Adhesion GPCR VLGR1/ADGRV1

by Barbara Knapp, Jens Roedig, Heiko Roedig, Jacek Krzysko, Nicola Horn, Baran E. Güler, Deva Krupakar Kusuluri, Adem Yildirim, Karsten Boldt, Marius Ueffing, Ines Liebscher and Uwe Wolfrum

Molecules 2022, 27(10), 3108; https://doi.org/10.3390/molecules27103108 - 12 May 2022

Cited by 8 | Viewed by 3816

Abstract

The very large G-protein-coupled receptor 1 (VLGR1/ADGRV1) is the largest member of the adhesion G-protein-coupled receptor (ADGR) family. Mutations in VLGR1/ADGRV1 cause human Usher syndrome (USH), a form of hereditary deaf-blindness, and have been additionally linked to epilepsy. In the absence of tangible [...] Read more.

The very large G-protein-coupled receptor 1 (VLGR1/ADGRV1) is the largest member of the adhesion G-protein-coupled receptor (ADGR) family. Mutations in VLGR1/ADGRV1 cause human Usher syndrome (USH), a form of hereditary deaf-blindness, and have been additionally linked to epilepsy. In the absence of tangible knowledge of the molecular function and signaling of VLGR1, the pathomechanisms underlying the development of these diseases are still unknown. Our study aimed to identify novel, previously unknown protein networks associated with VLGR1 in order to describe new functional cellular modules of this receptor. Using affinity proteomics, we have identified numerous new potential binding partners and ligands of VLGR1. Tandem affinity purification hits were functionally grouped based on their Gene Ontology terms and associated with functional cellular modules indicative of functions of VLGR1 in transcriptional regulation, splicing, cell cycle regulation, ciliogenesis, cell adhesion, neuronal development, and retinal maintenance. In addition, we validated the identified protein interactions and pathways in vitro and in situ. Our data provided new insights into possible functions of VLGR1, related to the development of USH and epilepsy, and also suggest a possible role in the development of other neuronal diseases such as Alzheimer’s disease. Full article

(This article belongs to the Special Issue Molecular Modeling, Synthesis, and Functional Characterization of GPCR (G-Protein Coupled Receptor) Ligands)

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12 pages, 2337 KiB

Open AccessEditor’s ChoiceArticle

Interaction Structure and Affinity of Zwitterionic Amino Acids with Important Metal Cations (Cd²⁺, Cu²⁺, Fe³⁺, Hg²⁺, Mn²⁺, Ni²⁺ and Zn²⁺) in Aqueous Solution: A Theoretical Study

by Xinning Liu, Menghan Wu, Chenchen Li, Peng Yu, Shanshan Feng, Yanwei Li and Qingzhu Zhang

Molecules 2022, 27(8), 2407; https://doi.org/10.3390/molecules27082407 - 8 Apr 2022

Cited by 16 | Viewed by 2411

Abstract

Heavy metals are non-biodegradable and carcinogenic pollutants with great bio-accumulation potential. Their ubiquitous occurrence in water and soils has caused serious environmental concerns. Effective strategies that can eliminate the heavy metal pollution are urgently needed. Here the adsorption potential of seven heavy metal [...] Read more.

Heavy metals are non-biodegradable and carcinogenic pollutants with great bio-accumulation potential. Their ubiquitous occurrence in water and soils has caused serious environmental concerns. Effective strategies that can eliminate the heavy metal pollution are urgently needed. Here the adsorption potential of seven heavy metal cations (Cd²⁺, Cu²⁺, Fe³⁺, Hg²⁺, Mn²⁺, Ni²⁺ and Zn²⁺) with 20 amino acids was systematically investigated with Density Functional Theory method. The binding energies calculated at B3LYP-D3/def2TZVP level showed that the contribution order of amino acid side chains to the binding affinity was carboxyl > benzene ring > hydroxyl > sulfhydryl > amino group. The affinity order was inversely proportional to the radius and charge transfer of heavy metal cations, approximately following the order of: Ni²⁺ > Fe³⁺ > Cu²⁺ > Hg²⁺ > Zn²⁺ > Cd²⁺ > Mn²⁺. Compared to the gas-phase in other researches, the water environment has a significant influence on structures and binding energies of the heavy metal and amino acid binary complexes. Collectively, the present results will provide a basis for the design of a chelating agent (e.g., adding carboxyl or a benzene ring) to effectively remove heavy metals from the environment. Full article

(This article belongs to the Section Computational and Theoretical Chemistry)

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11 pages, 10968 KiB

Open AccessEditor’s ChoiceArticle

Synthesis and Reactivity of Manganese Complexes Bearing Anionic PNP- and PCP-Type Pincer Ligands toward Nitrogen Fixation

by Shogo Kuriyama, Shenglan Wei, Takeru Kato and Yoshiaki Nishibayashi

Molecules 2022, 27(7), 2373; https://doi.org/10.3390/molecules27072373 - 6 Apr 2022

Cited by 5 | Viewed by 2895

Abstract

A series of manganese complexes bearing an anionic pyrrole-based PNP-type pincer ligand and an anionic benzene-based PCP-type pincer ligand is synthesized and characterized. The reactivity of these complexes toward ammonia formation and silylamine formation from dinitrogen under mild conditions is evaluated to produce [...] Read more.

A series of manganese complexes bearing an anionic pyrrole-based PNP-type pincer ligand and an anionic benzene-based PCP-type pincer ligand is synthesized and characterized. The reactivity of these complexes toward ammonia formation and silylamine formation from dinitrogen under mild conditions is evaluated to produce only stoichiometric amounts of ammonia and silylamine, probably because the manganese pincer complexes are unstable under reducing conditions. Full article

(This article belongs to the Special Issue Design Strategies for Metal Complexes that Activate Bio-Related Small Molecules)

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20 pages, 5892 KiB

Open AccessEditor’s ChoiceArticle

An Expeditious Approach towards the Synthesis and Application of Water-Soluble and Photostable Fluorogenic Chromones for DNA Detection

by Steve Vincent, Suman Mallick, Guillaume Barnoin, Hoang-Ngoan Le, Benoît Y. Michel and Alain Burger

Molecules 2022, 27(7), 2267; https://doi.org/10.3390/molecules27072267 - 31 Mar 2022

Cited by 3 | Viewed by 1920

Abstract

The intensive research for hybridization probes based on organic molecules with fluorogenic properties is currently attracting particular attention due to their potential to efficiently recognize different DNA conformations and the local environment. However, most established organic chromophores do not meet the requirements of [...] Read more.

The intensive research for hybridization probes based on organic molecules with fluorogenic properties is currently attracting particular attention due to their potential to efficiently recognize different DNA conformations and the local environment. However, most established organic chromophores do not meet the requirements of this task, as they do not exhibit good brightness in aqueous buffer media, develop aggregation and/or are not easily conjugated to oligodeoxynucleotides (ODNs) while keeping their photophysics intact. Herein, an important modification strategy was employed for a well-known fluorophore, 2-(4-(diethylamino)phenyl)-3-hydroxychromone (dEAF). Although this push–pull dye absorbs intensively in the visible range and shows emission with large Stokes shifts in all organic solvents, it is strongly quenched in water. This Achilles’ heel prompted us to implement a new strategy to obtain a series of dyes that retain all the photophysical features of dEAF in water, conjugate readily with oligonucleotides, and furthermore demonstrate sensitivity to hydration, thus paving the way for a high-performance fluorogenic DNA hybridization probe. Full article

(This article belongs to the Special Issue Fluorescent Probes in Pharmaceutical and Drug Design Applications: Quantum Chemistry-Based Design, Synthesis, Photophysical and Chemical Properties, Biological Applications)

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11 pages, 3708 KiB

Open AccessEditor’s ChoiceArticle

Iridium(I)-Catalyzed Isoindolinone-Directed Branched-Selective Aromatic C–H Alkylation with Simple Alkenes

by Maoqian Xiong, Yuhang Shu, Jie Tang, Fan Yang and Dong Xing

Molecules 2022, 27(6), 1923; https://doi.org/10.3390/molecules27061923 - 16 Mar 2022

Cited by 5 | Viewed by 2125

Abstract

We report an iridium(I)-catalyzed branched-selective C–H alkylation of N-arylisoindolinones with simple alkenes as the alkylating agents. The amide carbonyl group of the isoindolinone motif acts as the directing group to assist the ortho C–H activation of the N-aryl ring. With this [...] Read more.

We report an iridium(I)-catalyzed branched-selective C–H alkylation of N-arylisoindolinones with simple alkenes as the alkylating agents. The amide carbonyl group of the isoindolinone motif acts as the directing group to assist the ortho C–H activation of the N-aryl ring. With this atom-economic and highly branched-selective protocol, an array of biologically relevant N-arylisoindolinones were obtained in good yields. Asymmetric control was achieved with up to 87:13 er when a BiPhePhos-like chiral ligand was employed. Full article

(This article belongs to the Section Organic Chemistry)

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13 pages, 2711 KiB

Open AccessEditor’s ChoiceArticle

Investigating the Effects of Amino Acid Variations in Human Menin

by Carmen Biancaniello, Antonia D’Argenio, Deborah Giordano, Serena Dotolo, Bernardina Scafuri, Anna Marabotti, Antonio d’Acierno, Roberto Tagliaferri and Angelo Facchiano

Molecules 2022, 27(5), 1747; https://doi.org/10.3390/molecules27051747 - 7 Mar 2022

Cited by 7 | Viewed by 3318

Abstract

Human menin is a nuclear protein that participates in many cellular processes, as transcriptional regulation, DNA damage repair, cell signaling, cell division, proliferation, and migration, by interacting with many other proteins. Mutations of the gene encoding menin cause multiple endocrine neoplasia type 1 [...] Read more.

Human menin is a nuclear protein that participates in many cellular processes, as transcriptional regulation, DNA damage repair, cell signaling, cell division, proliferation, and migration, by interacting with many other proteins. Mutations of the gene encoding menin cause multiple endocrine neoplasia type 1 (MEN1), a rare autosomal dominant disorder associated with tumors of the endocrine glands. In order to characterize the structural and functional effects at protein level of the hundreds of missense variations, we investigated by computational methods the wild-type menin and more than 200 variants, predicting the amino acid variations that change secondary structure, solvent accessibility, salt-bridge and H-bond interactions, protein thermostability, and altering the capability to bind known protein interactors. The structural analyses are freely accessible online by means of a web interface that integrates also a 3D visualization of the structure of the wild-type and variant proteins. The results of the study offer insight into the effects of the amino acid variations in view of a more complete understanding of their pathological role. Full article

(This article belongs to the Special Issue Molecular Simulations Applications in Biochemistry and Molecular Biology)

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29 pages, 6922 KiB

Open AccessEditor’s ChoiceArticle

Tuning Photophysical Properties by p-Functional Groups in Zn(II) and Cd(II) Complexes with Piperonylic Acid

by Francisco Sánchez-Férez, Joaquim Mª Rius-Bartra, José A. Ayllón, Teresa Calvet, Mercè Font-Bardia and Josefina Pons

Molecules 2022, 27(4), 1365; https://doi.org/10.3390/molecules27041365 - 17 Feb 2022

Cited by 12 | Viewed by 2439

Abstract

Aggregation between discrete molecules is an essential factor to prevent aggregation-caused quenching (ACQ). Indeed, functional groups capable of generating strong hydrogen bonds are likely to assemble and cause ACQ and photoinduced electron transfer processes. Thus, it is possible to compare absorption and emission [...] Read more.

Aggregation between discrete molecules is an essential factor to prevent aggregation-caused quenching (ACQ). Indeed, functional groups capable of generating strong hydrogen bonds are likely to assemble and cause ACQ and photoinduced electron transfer processes. Thus, it is possible to compare absorption and emission properties by incorporating two ligands with a different bias toward intra- and intermolecular interactions that can induce a specific structural arrangement. In parallel, the π electron-donor or electron-withdrawing character of the functional groups could modify the Highest Ocuppied Molecular Orbital (HOMO)–Lowest Unocuppied Molecular Orbital (LUMO) energy gap. Reactions of M(OAc)₂·2H₂O (M = Zn(II) and Cd(II); OAc = acetate) with 1,3-benzodioxole-5-carboxylic acid (Piperonylic acid, HPip) and 4-acetylpyridine (4-Acpy) or isonicotinamide (Isn) resulted in the formation of four complexes. The elucidation of their crystal structure showed the formation of one paddle-wheel [Zn(μ-Pip)₂(4-Acpy)]₂ (1); a mixture of one dimer and two monomers [Zn(µ-Pip)(Pip)(Isn)₂]₂·2[Zn(Pip)₂(HPip)(Isn)]·2MeOH (2); and two dimers [Cd(μ-Pip)(Pip)(4-Acpy)₂]₂ (3) and [Cd(μ-Pip)(Pip)(Isn)₂]₂·MeOH (4). They exhibit bridged (1, µ₂-η¹:η¹), bridged, chelated and monodentated (2, µ₂-η¹:η¹, µ₁-η¹:η¹ and µ₁-η¹), or simultaneously bridged and chelated (3 and 4, µ₂-η²:η¹) coordination modes. Zn(II) centers accommodate coordination numbers 5 and 6, whereas Cd(II) presents coordination number 7. We have related their photophysical properties and fluorescence quantum yields with their geometric variations and interactions supported by TD-DFT calculations. Full article

(This article belongs to the Special Issue Nitrogen Ligands)

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15 pages, 12257 KiB

Open AccessEditor’s ChoiceArticle

Photoinduced Bisphosphination of Alkynes with Phosphorus Interelement Compounds and Its Application to Double-Bond Isomerization

by Yuki Yamamoto, Ryo Tanaka, Shintaro Kodama, Akihiro Nomoto and Akiya Ogawa

Molecules 2022, 27(4), 1284; https://doi.org/10.3390/molecules27041284 - 14 Feb 2022

Cited by 7 | Viewed by 2242

Abstract

The addition of interelement compounds with heteroatom-heteroatom single bonds to carbon-carbon unsaturated bonds under light irradiation is believed to be an atomically efficient method to procure materials with carbon-heteroatom bonds. In this study, we achieved the photoinduced bisphosphination of alkynes using the phosphorus [...] Read more.

The addition of interelement compounds with heteroatom-heteroatom single bonds to carbon-carbon unsaturated bonds under light irradiation is believed to be an atomically efficient method to procure materials with carbon-heteroatom bonds. In this study, we achieved the photoinduced bisphosphination of alkynes using the phosphorus interelement compound, tetraphenyldiphosphine monosulfide (1), to stereoselectively obtain the corresponding (E)-vic-1,2-bisphosphinoalkenes, which are important transition-metal ligands. The bisphosphination reaction was performed by mixing 1 and various alkynes and then exposing the mixture to light irradiation. Optimization of the conditions for the bisphosphination reaction resulted in a wide substrate range and excellent trans-selectivity. Moreover, the completely regioselective introduction of pentavalent and trivalent phosphorus groups to the terminal and internal positions of the alkynes, respectively, was achieved. We also found that the novel double-bond isomerization reaction of the synthesized bisphosphinated products occurred with a catalytic amount of a base under mild conditions. Our method for the photoinduced bisphosphination of carbon-carbon unsaturated compounds may have strong implications for both organic synthesis and organometallic and catalyst chemistry. Full article

(This article belongs to the Special Issue Modern Organophosphorus Chemistry)

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19 pages, 8596 KiB

Open AccessEditor’s ChoiceArticle

Identification of a Common Pharmacophore for Binding to MMP2 and RGD Integrin: Towards a Multitarget Approach to Inhibit Cancer Angiogenesis and Metastasis

by Lorenzo Baldini, Elena Lenci, Francesca Bianchini and Andrea Trabocchi

Molecules 2022, 27(4), 1249; https://doi.org/10.3390/molecules27041249 - 12 Feb 2022

Cited by 4 | Viewed by 2990

Abstract

During tumor angiogenesis different growth factors, cytokines and other molecules interact closely with each other to facilitate tumor cell invasion and metastatic diffusion. The most intensively studied as molecular targets in anti-angiogenic therapies are vascular endothelial growth factor (VEGF) and related receptors, integrin [...] Read more.

During tumor angiogenesis different growth factors, cytokines and other molecules interact closely with each other to facilitate tumor cell invasion and metastatic diffusion. The most intensively studied as molecular targets in anti-angiogenic therapies are vascular endothelial growth factor (VEGF) and related receptors, integrin receptors and matrix metalloproteinases (MMPs). Considering the poor efficacy of cancer angiogenesis monotherapies, we reasoned combining the inhibition of α_vβ₃ and MMP2 as a multitarget approach to deliver a synergistic blockade of tumor cell migration, invasion and metastasis. Accordingly, we identified a common pharmacophore in the binding cavity of MMP2 and α_vβ₃, demonstrating such approach with the design, synthesis and bioassays of tyrosine-derived peptidomimetics carrying the necessary functional groups to bind to key pharmacophoric elements of MMP2 and α_vβ₃ RGD integrin. Full article

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

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17 pages, 6023 KiB

Open AccessEditor’s ChoiceArticle

Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations

by Shihao Yao, Boyuan Ma, Qiuzi Yi, Min-Xin Guan and Xiaohui Cang

Molecules 2022, 27(3), 1071; https://doi.org/10.3390/molecules27031071 - 5 Feb 2022

Cited by 6 | Viewed by 2418

Abstract

The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge [...] Read more.

The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge on these networks is still limited. In the current work, we focus on more conserved m-gate network in the c-state AAC. All-atom molecular dynamics (MD) simulations on a variety of mutants and the CATR-AAC complex have revealed that: (1) without involvement of other positive residues, the charged residues from the three Px[DE]xx[KR] motifs only are prone to form symmetrical inter-helical network; (2) R235 plays a determinant role for the asymmetry in m-gate network of AAC; (3) R235 significantly strengthens the interactions between H3 and H5; (4) R79 exhibits more significant impact on m-gate than R279; (5) CATR promotes symmetry in m-gate mainly through separating R234 from D231 and fixing R79; (6) vulnerability of the H2-H3 interface near matrix side could be functionally important. Our results provide new insights into the highly conserved yet variable m-gate network in the big mitochondrial carrier family. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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16 pages, 3290 KiB

Open AccessEditor’s ChoiceArticle

The Mechanism of a Retro-Diels–Alder Fragmentation of Luteolin: Theoretical Studies Supported by Electrospray Ionization Tandem Mass Spectrometry Results

by Magdalena Śliwka-Kaszyńska, Iwona Anusiewicz and Piotr Skurski

Molecules 2022, 27(3), 1032; https://doi.org/10.3390/molecules27031032 - 3 Feb 2022

Cited by 18 | Viewed by 2517

Abstract

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 [...] Read more.

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

(This article belongs to the Section Computational and Theoretical Chemistry)

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14 pages, 3919 KiB

Open AccessEditor’s ChoiceArticle

Hydrogen Bonds with Fluorine in Ligand–Protein Complexes-the PDB Analysis and Energy Calculations

by Wojciech Pietruś, Rafał Kafel, Andrzej J. Bojarski and Rafał Kurczab

Molecules 2022, 27(3), 1005; https://doi.org/10.3390/molecules27031005 - 2 Feb 2022

Cited by 19 | Viewed by 3078

Abstract

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 [...] Read more.

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

(This article belongs to the Collection Hydrogen Bonds)

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15 pages, 2811 KiB

Open AccessEditor’s ChoiceArticle

Straightforward Access to Enantioenriched cis-3-Fluoro-dihydroquinolin-4-ols Derivatives via Ru(II)-Catalyzed-Asymmetric Transfer Hydrogenation/Dynamic Kinetic Resolution

by Ricardo Molina Betancourt, Phannarath Phansavath and Virginie Ratovelomanana-Vidal

Molecules 2022, 27(3), 995; https://doi.org/10.3390/molecules27030995 - 1 Feb 2022

Cited by 7 | Viewed by 2051

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue A Wonderful Journey in the Asymmetric Catalysis World: A Themed Issue in Honor of Prof. Henri B. Kagan)

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19 pages, 3770 KiB

Open AccessEditor’s ChoiceArticle

Mechanistic Characterization of the Pharmacological Profile of HS-731, a Peripherally Acting Opioid Analgesic, at the µ-, δ-, κ-Opioid and Nociceptin Receptors

by Kristina Puls, Helmut Schmidhammer, Gerhard Wolber and Mariana Spetea

Molecules 2022, 27(3), 919; https://doi.org/10.3390/molecules27030919 - 28 Jan 2022

Cited by 8 | Viewed by 2698

Abstract

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, [...] Read more.

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

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery II)

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14 pages, 3050 KiB

Open AccessEditor’s ChoiceArticle

Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action

by Peter Jaein Choi, Petr Tomek, Moana Tercel, Jóhannes Reynisson, Thomas In Hyeup Park, Elizabeth Alexandra Cooper, William Alexander Denny, Jiney Jose and Euphemia Leung

Molecules 2022, 27(3), 880; https://doi.org/10.3390/molecules27030880 - 27 Jan 2022

Cited by 6 | Viewed by 3693

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)

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26 pages, 39190 KiB

Open AccessEditor’s ChoiceArticle

Structural Properties and Magnetic Ground States of 100 Binary d-Metal Oxides Studied by Hybrid Density Functional Methods

by Mikhail S. Kuklin, Kim Eklund, Jarno Linnera, Artturi Ropponen, Nikolas Tolvanen and Antti J. Karttunen

Molecules 2022, 27(3), 874; https://doi.org/10.3390/molecules27030874 - 27 Jan 2022

Cited by 16 | Viewed by 4156

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue A Commemorative Special Issue Honoring Professor Donald Truhlar)

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13 pages, 2358 KiB

Open AccessEditor’s ChoiceArticle

Comparison of Proton Acceptor and Proton Donor Properties of H₂O and H₂O₂ in Organic Crystals of Drug-like Compounds: Peroxosolvates vs. Crystallohydrates

by Mikhail V. Vener, Andrei V. Churakov, Alexander P. Voronin, Olga D. Parashchuk, Sergei V. Artobolevskii, Oleg A. Alatortsev, Denis E. Makhrov, Alexander G. Medvedev and Aleksander Filarowski

Molecules 2022, 27(3), 717; https://doi.org/10.3390/molecules27030717 - 22 Jan 2022

Cited by 12 | Viewed by 2374

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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17 pages, 13616 KiB

Open AccessEditor’s ChoiceArticle

DrugDevCovid19: An Atlas of Anti-COVID-19 Compounds Derived by Computer-Aided Drug Design

by Yang Liu, Jianhong Gan, Rongqi Wang, Xiaocong Yang, Zhixiong Xiao and Yang Cao

Molecules 2022, 27(3), 683; https://doi.org/10.3390/molecules27030683 - 21 Jan 2022

Cited by 12 | Viewed by 3476

Abstract

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 [...] Read more.

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

(This article belongs to the Section Computational and Theoretical Chemistry)

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15 pages, 2003 KiB

Open AccessEditor’s ChoiceArticle

Synthesis and Biological Investigation of Bile Acid-Paclitaxel Hybrids

by Elisabetta Melloni, Elena Marchesi, Lorenzo Preti, Fabio Casciano, Erika Rimondi, Arianna Romani, Paola Secchiero, Maria Luisa Navacchia and Daniela Perrone

Molecules 2022, 27(2), 471; https://doi.org/10.3390/molecules27020471 - 12 Jan 2022

Cited by 12 | Viewed by 2543

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Frontiers in Bile Acid Chemistry and Applications)

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18 pages, 6293 KiB

Open AccessEditor’s ChoiceArticle

In Silico Prediction and Validation of CB2 Allosteric Binding Sites to Aid the Design of Allosteric Modulators

by Jiayi Yuan, Chen Jiang, Junmei Wang, Chih-Jung Chen, Yixuan Hao, Guangyi Zhao, Zhiwei Feng and Xiang-Qun Xie

Molecules 2022, 27(2), 453; https://doi.org/10.3390/molecules27020453 - 11 Jan 2022

Cited by 14 | Viewed by 3035

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Simulational and Computational Approaches to Enhance Protein Inhibitor Designs)

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13 pages, 5166 KiB

Open AccessEditor’s ChoiceArticle

Photoredox-Catalyzed Giese Reactions: Decarboxylative Additions to Cyclic Vinylogous Amides and Esters

by Kevin Dykstra, Alexei Buevich, Qi Gao, Yu-Hong Lam and Jeffrey T. Kuethe

Molecules 2022, 27(2), 417; https://doi.org/10.3390/molecules27020417 - 10 Jan 2022

Viewed by 1898

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Heterocyclic and Organometallic Chemistry: Theme Issue in Honor of Prof. Daniel Comins’ Great Contribution)

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15 pages, 800 KiB

Open AccessEditor’s ChoiceArticle

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

by José P. Coelho, Maria P. Robalo, Stanislava Boyadzhieva and Roumiana P. Stateva

Molecules 2021, 26(23), 7320; https://doi.org/10.3390/molecules26237320 - 2 Dec 2021

Cited by 13 | Viewed by 3467

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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45 pages, 8578 KiB

Open AccessEditor’s ChoiceArticle

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

by Nigel Vicker, Helen V. Bailey, Joanna M. Day, Mary F. Mahon, Andrew Smith, Helena J. Tutill, Atul Purohit and Barry V. L. Potter

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

Cited by 1 | Viewed by 3550

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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20 pages, 5324 KiB

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, Selvaraj Alagu Lakshmi, Shunmugiah Karutha Pandian, Young-Mo Kim, Joseph Deutsch, Elena Katrich and Shela Gorinstein

Molecules 2021, 26(21), 6686; https://doi.org/10.3390/molecules26216686 - 5 Nov 2021

Cited by 10 | Viewed by 2987

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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28 pages, 8098 KiB

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

by Laia Josa-Culleré, Thomas J. Cogswell, Irene Georgiou, Morgan Jay-Smith, Thomas R. Jackson, Carole J. R. Bataille, Stephen G. Davies, Paresh Vyas, Thomas A. Milne, Graham M. Wynne and Angela J. Russell

Molecules 2021, 26(21), 6648; https://doi.org/10.3390/molecules26216648 - 2 Nov 2021

Viewed by 2889

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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21 pages, 3909 KiB

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 6 | Viewed by 3990

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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18 pages, 5812 KiB

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

by Jhao-Ru Lai, Ya-Wen Hsu, Tzu-Ming Pan and Chun-Lin Lee

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

Cited by 22 | Viewed by 4662

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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19 pages, 847 KiB

Open AccessEditor’s ChoiceArticle

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

by Mastaneh Safarnejad Shad, Sandra Claes, Eline Goffin, Tom Van Loy, Dominique Schols, Steven De Jonghe and Wim Dehaen

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

Cited by 3 | Viewed by 2510

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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41 pages, 6162 KiB

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 20 | Viewed by 8387

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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18 pages, 3110 KiB

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, Marco Martín González-Chávez, Francisco Méndez, Arlette Richaud, Rodolfo González-Chávez, Luis Enrique Ojeda-Fuentes, Perla del Carmen Niño-Moreno and Roberto Martínez

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

Cited by 4 | Viewed by 3079

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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