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Synthesis and Molecular Recognition of Macrocyclic Compounds

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Applied Chemistry".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 29023

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Guest Editor
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Szent Gellért tér 4, 1111 Budapest, Hungary
Interests: synthesis and molecular recognition of macrocycles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The molecular recognition of biomolecules is a ubiquitous and vital phenomenon in nature. This phenomenon can also be engineered into synthetic molecules such as macrocycles.

Studies on molecular recognition using macrocycles such as crown ethers, cryptands, calixarenes, cyclodextrin derivatives, spherands, cavitands, cyclophanes, cucurbiturils, catenanes, rotaxanes, and many others are not only important because they help us to better understand its working in nature, but also because these studies can lead to the development of effective sensor and selector molecules and catalysts with wide applications.

This Special Issue focuses on the synthesis and molecular recognition of macrocycles and their applications as sensors, selectors, and catalysts.

Prof. Dr. Peter Huszthy
Guest Editor

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Keywords

  • synthesis;
  • host–guest interaction;
  • thermodynamic parameters;
  • kinetic parameters;
  • sensor molecules;
  • selector molecules;
  • catalysts;
  • medical applications;
  • industrial applications.

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Published Papers (11 papers)

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Research

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22 pages, 5950 KiB  
Article
Effect of Cyclodextrins on the Biofilm Formation Capacity of Pseudomonas aeruginosa PAO1
by Zsófia Berkl, Ildikó Fekete-Kertész, Kata Buda, Emese Vaszita, Éva Fenyvesi, Lajos Szente and Mónika Molnár
Molecules 2022, 27(11), 3603; https://doi.org/10.3390/molecules27113603 - 3 Jun 2022
Cited by 4 | Viewed by 2124
Abstract
Quorum sensing (QS) is a population-density-dependent communication process of microorganisms to coordinate their activities by producing and detecting low-molecular-weight signal molecules. In pathogenic bacteria, the property controlled by QS is often related to infectivity, e.g., biofilm formation. Molecular encapsulation of the QS signals [...] Read more.
Quorum sensing (QS) is a population-density-dependent communication process of microorganisms to coordinate their activities by producing and detecting low-molecular-weight signal molecules. In pathogenic bacteria, the property controlled by QS is often related to infectivity, e.g., biofilm formation. Molecular encapsulation of the QS signals is an innovative method to prevent the signals binding to the receptors and to attenuate QS. Cyclodextrins (CDs) may form an inclusion complex with the signals, thus reducing the communication (quorum quenching, QQ). A systematic study was performed with α-, β-cyclodextrin, and their random methylated, quaternary amino and polymer derivatives to evaluate and compare their effects on the biofilm formation of Pseudomonas aeruginosa. To examine the concentration-, temperature- and time-dependency of the QQ effect, the CDs were applied at a 0.1–12.5 mM concentration range, and biofilm formation was studied after 6, 24, 48 and 72 h at 22 and 30 °C. According to the results, the QS mechanism was significantly inhibited; the size of the cavity, the structure of the substituents, as well as the monomeric or polymeric character together with the concentration of the CDs have been identified as key influencing factors of biofilm formation. Statistically determined effective concentration values demonstrated outstanding efficiency (higher than 80% inhibition) of α-CD and its random methylated and polymer derivatives both on the short and long term. In summary, the potential value of CDs as inhibitors of QS should be considered since the inhibition of biofilm formation could significantly impact human health and the environment. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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14 pages, 1344 KiB  
Article
Covalently Immobilizable Tris(Pyridino)-Crown Ether for Separation of Amines Based on Their Degree of Substitution
by Panna Vezse, Bianka Benda, András Fekete, Ádám Golcs, Tünde Tóth and Péter Huszthy
Molecules 2022, 27(9), 2838; https://doi.org/10.3390/molecules27092838 - 29 Apr 2022
Cited by 5 | Viewed by 1858
Abstract
A great number of biologically active compounds contain at least one amine function. Appropriate selectivity can only be accomplished in a few cases upon the substitution of these groups, thus functionalization of amines generally results in a mixture of them. The separation of [...] Read more.
A great number of biologically active compounds contain at least one amine function. Appropriate selectivity can only be accomplished in a few cases upon the substitution of these groups, thus functionalization of amines generally results in a mixture of them. The separation of these derivatives with very similar characteristics can only be performed on a preparative scale or by applying pre-optimized HPLC methods. A tris(pyridino)-crown ether was designed and synthetized for overcoming these limitations at a molecular level. It is demonstrated, that this selector molecule is able to distinguish protonated primary, secondary and tertiary amines by the formation of reversible complexes with different stabilities. This degree of substitution-specific molecular recognition of amines opens the door to develop separation processes primarily focusing on the purification of biologically active compounds in a nanomolar scale. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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11 pages, 2554 KiB  
Article
Chiral Recognition of Amino Acid Esters in Organic Solvents Using a Glucose-Based Receptor
by Leah Susanne Mönkemöller, Martin Schnurr and Bartosz Lewandowski
Molecules 2022, 27(7), 2177; https://doi.org/10.3390/molecules27072177 - 28 Mar 2022
Cited by 1 | Viewed by 2235
Abstract
Due to the chemical and biological relevance of amino acids, efficient methods for the recognition and separation of their enantiomers are highly sought after. Chiral receptors based on extended molecular scaffolds are typically employed for this purpose. These receptors are often effective only [...] Read more.
Due to the chemical and biological relevance of amino acids, efficient methods for the recognition and separation of their enantiomers are highly sought after. Chiral receptors based on extended molecular scaffolds are typically employed for this purpose. These receptors are often effective only in specific environments and towards a narrow scope of amino acid guests. Recently we reported a simple, glucose-based macrocycle capable of enantioselective binding of a broad range of amino acid methyl esters in water. Herein we demonstrate that the same receptor can be used for chiral recognition of amino acid esters in organic solvents. We show that the binding affinity and selectivity of the receptor are highly dependent on the coordinating strength of the solvent. An in-depth analysis of the receptor’s conformation and its interactions with amino acid methyl esters allowed us to propose a binding mode of amino acids to the receptor in CDCl3. The binding modes in CDCl3 and D2O were then compared, highlighting the main interactions responsible for binding affinity and selectivity in each solvent. We envision that the insight provided by this study will facilitate the development of further amino acid receptors based on monosaccharides with improved binding affinities and both enantio- as well as chemoselectivities. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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27 pages, 3719 KiB  
Article
A New Oxygen Containing Pyclen-Type Ligand as a Manganese(II) Binder for MRI and 52Mn PET Applications: Equilibrium, Kinetic, Relaxometric, Structural and Radiochemical Studies
by Tibor Csupász, Dániel Szücs, Ferenc Krisztián Kálmán, Oldamur Hollóczki, Anikó Fekete, Dezső Szikra, Éva Tóth, Imre Tóth and Gyula Tircsó
Molecules 2022, 27(2), 371; https://doi.org/10.3390/molecules27020371 - 7 Jan 2022
Cited by 9 | Viewed by 2994
Abstract
A new pyclen-3,9-diacetate derivative ligand (H23,9-OPC2A) was synthesized possessing an etheric O-atom opposite to the pyridine ring, to improve the dissociation kinetics of its Mn(II) complex (pyclen = 3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene). The new ligand is less basic than the N-containing analogue (H [...] Read more.
A new pyclen-3,9-diacetate derivative ligand (H23,9-OPC2A) was synthesized possessing an etheric O-atom opposite to the pyridine ring, to improve the dissociation kinetics of its Mn(II) complex (pyclen = 3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene). The new ligand is less basic than the N-containing analogue (H23,9-PC2A) due to the non-protonable O-atom. In spite of its lower basicity, the conditional stability of the [Mn(3,9-OPC2A)] (pMn = −log(Mn(II)), cL = cMn(II) = 0.01 mM. pH = 7.4) remains unaffected (pMn = 8.69), compared to the [Mn(3,9-PC2A)] (pMn = 8.64). The [Mn(3,9-OPC2A)] possesses one water molecule, having a lower exchange rate with bulk solvents (kex298 = 5.3 ± 0.4 × 107 s−1) than [Mn(3,9-PC2A)] (kex298 = 1.26 × 108 s−1). These mild differences are rationalized by density-functional theory (DFT) calculations. The acid assisted dissociation of [Mn(3,9-OPC2A)] is considerably slower (k1 = 2.81 ± 0.07 M−1 s−1) than that of the complexes of diacetates or bisamides of various 12-membered macrocycles and the parent H23,9-PC2A. The [Mn(3,9-OPC2A)] is inert in rat/human serum as confirmed by 52Mn labeling (nM range), as well as by relaxometry (mM range). However, a 600-fold excess of EDTA (pH = 7.4) or a mixture of essential metal ions, propagated some transchelation/transmetalation in 7 days. The H23,9-OPC2A is labeled efficiently with 52Mn at elevated temperatures, yet at 37 °C the parent H23,9-PC2A performs slightly better. Ultimately, the H23,9-OPC2A shows advantageous features for further ligand designs for bifunctional chelators. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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11 pages, 18958 KiB  
Article
A Dispersion Corrected DFT Investigation of the Inclusion Complexation of Dexamethasone with β-Cyclodextrin and Molecular Docking Study of Its Potential Activity against COVID-19
by Youghourta Belhocine, Seyfeddine Rahali, Hamza Allal, Ibtissem Meriem Assaba, Monira Galal Ghoniem and Fatima Adam Mohamed Ali
Molecules 2021, 26(24), 7622; https://doi.org/10.3390/molecules26247622 - 15 Dec 2021
Cited by 11 | Viewed by 2792
Abstract
The encapsulation mode of dexamethasone (Dex) into the cavity of β-cyclodextrin (β-CD), as well as its potential as an inhibitor of the COVID-19 main protease, were investigated using density functional theory with the recent dispersion corrections D4 and molecular docking calculations. Independent gradient [...] Read more.
The encapsulation mode of dexamethasone (Dex) into the cavity of β-cyclodextrin (β-CD), as well as its potential as an inhibitor of the COVID-19 main protease, were investigated using density functional theory with the recent dispersion corrections D4 and molecular docking calculations. Independent gradient model and natural bond orbital approaches allowed for the characterization of the host–guest interactions in the studied systems. Structural and energetic computation results revealed that hydrogen bonds and van der Waals interactions played significant roles in the stabilization of the formed Dex@β-CD complex. The complexation energy significantly decreased from −179.50 kJ/mol in the gas phase to −74.14 kJ/mol in the aqueous phase. A molecular docking study was performed to investigate the inhibitory activity of dexamethasone against the COVID-19 target protein (PDB ID: 6LU7). The dexamethasone showed potential therapeutic activity as a SARS CoV-2 main protease inhibitor due to its strong binding to the active sites of the protein target, with predicted free energy of binding values of −29.97 and −32.19 kJ/mol as calculated from AutoDock4 and AutoDock Vina, respectively. This study was intended to explore the potential use of the Dex@β-CD complex in drug delivery to enhance dexamethasone dissolution, thus improving its bioavailability and reducing its side effects. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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13 pages, 2584 KiB  
Article
DFT-D4 Insight into the Inclusion of Amphetamine and Methamphetamine in Cucurbit[7]uril: Energetic, Structural and Biosensing Properties
by Abdelkarim Litim, Youghourta Belhocine, Tahar Benlecheb, Monira Galal Ghoniem, Zoubir Kabouche, Fatima Adam Mohamed Ali, Babiker Yagoub Abdulkhair, Mahamadou Seydou and Seyfeddine Rahali
Molecules 2021, 26(24), 7479; https://doi.org/10.3390/molecules26247479 - 10 Dec 2021
Cited by 14 | Viewed by 3032
Abstract
The host–guest interactions of cucurbit[7]uril (CB[7]) as host and amphetamine (AMP), methamphetamine (MET) and their enantiomeric forms (S-form and R-form) as guests were computationally investigated using density functional theory calculations with the recent D4 atomic-charge dependent dispersion corrections. The analysis of energetic, structural [...] Read more.
The host–guest interactions of cucurbit[7]uril (CB[7]) as host and amphetamine (AMP), methamphetamine (MET) and their enantiomeric forms (S-form and R-form) as guests were computationally investigated using density functional theory calculations with the recent D4 atomic-charge dependent dispersion corrections. The analysis of energetic, structural and electronic properties with the aid of frontier molecular orbital analysis, charge decomposition analysis (CDA), extended charge decomposition analysis (ECDA) and independent gradient model (IGM) approach allowed to characterize the host–guest interactions in the studied systems. Energetic results indicate the formation of stable non-covalent complexes where R-AMP@CB[7] and S-AMP@CB[7] are more stable thermodynamically than R-MET@CB[7] and S-MET@CB[7] in gas phase while the reverse is true in water solvent. Based on structural analysis, a recognition mechanism is proposed, which suggests that the synergistic effect of van der Waals forces, ion–dipole interactions, intermolecular charge transfer interactions and intermolecular hydrogen bonding is responsible for the stabilization of the complexes. The geometries of the complexes obtained theoretically are in good agreement with the X-ray experimental structures and indicate that the phenyl ring of amphetamine and methamphetamine is deeply buried into the cavity of CB[7] through hydrophobic interactions while the ammonium group remains outside the cavity to establish hydrogen bonds with the portal oxygen atoms of CB[7]. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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12 pages, 3655 KiB  
Article
NHC Polymeric Particles Obtained by Self-Assembly and Click Approach of Calix[4]Arene Amphiphiles as Support for Catalytically Active Pd Nanoclusters
by Vladimir Burilov, Diana Mironova, Elsa Sultanova, Ramila Garipova, Vladimir Evtugyn, Svetlana Solovieva and Igor Antipin
Molecules 2021, 26(22), 6864; https://doi.org/10.3390/molecules26226864 - 14 Nov 2021
Cited by 4 | Viewed by 2106
Abstract
A new polymeric NHC carrier was synthesized by sequential supramolecular self-assembly and copper-catalyzed azide-alkyne cycloaddition (CuAAC) of amphiphilic imidazolium calix[4]arenes with octyl lipophilic fragments. Obtained polytriazole-imidazolium particles were found as monodisperse submicron particles, with the average diameter of 236 ± 34 nm and [...] Read more.
A new polymeric NHC carrier was synthesized by sequential supramolecular self-assembly and copper-catalyzed azide-alkyne cycloaddition (CuAAC) of amphiphilic imidazolium calix[4]arenes with octyl lipophilic fragments. Obtained polytriazole-imidazolium particles were found as monodisperse submicron particles, with the average diameter of 236 ± 34 nm and average molecular weight of 1380 ± 96 kDa. Successful CuAAC polymerization has been proved using IR spectroscopy and high-resolution ESI mass spectrometry. Polymeric particles, as well as aggregates made from precursor macrocycles, were decorated by Pd clusters (2 nm) for further catalytic investigations. Pd nanoclusters, supported on the polymeric surface, were found highly catalytically active in the model reduction of p-nitrophenol, giving reaction rates an order of magnitude higher compared to literature examples. The reaction was recycled using the same catalyst five times without any loss of activity. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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15 pages, 1315 KiB  
Article
Synthesis of Methyl 4,6-Di-O-ethyl-α-d-glucopyranoside-Based Azacrown Ethers and Their Effects in Asymmetric Reactions
by István Orbán, Bertalan Varga, Péter Bagi, László Hegedűs, Péter Bakó and Zsolt Rapi
Molecules 2021, 26(15), 4668; https://doi.org/10.3390/molecules26154668 - 2 Aug 2021
Cited by 1 | Viewed by 2709
Abstract
Carbohydrate-based crown ethers have been reported to be able to generate asymmetric induction in certain reactions. Previously, it was proved that the monosaccharide unit, the anomeric substituent, and the sidearm could influence the catalytic activity of the monoaza-15-crown-5 macrocycles derived from sugars. In [...] Read more.
Carbohydrate-based crown ethers have been reported to be able to generate asymmetric induction in certain reactions. Previously, it was proved that the monosaccharide unit, the anomeric substituent, and the sidearm could influence the catalytic activity of the monoaza-15-crown-5 macrocycles derived from sugars. In order to gain information about the effect of the flexibility, 4,6-di-O-ethyl-glucoside-based crown compounds were synthesized, and their efficiency was compared to the 4,6-O-benzylidene analogues. It was found that the absence of the two-ring annulation has a negative effect on the enantioselectivity in liquid-liquid two-phase reactions: in the Darzens condensation of 2-chloroacetophenone and in the epoxidation of chalcone. The same trend was observed in the solid-liquid phase Michael addition of diethyl acetamidomalonate. Surprisingly, in the solid-liquid phase cyclopropanation of benzylidenemalononitrile, one of the new catalysts was highly enantioselective (99% ee). Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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20 pages, 3285 KiB  
Article
Acridino-Diaza-20-Crown-6 Ethers: New Macrocyclic Hosts for Optochemical Metal Ion Sensing
by Ádám Golcs, Korinna Kovács, Panna Vezse, Tünde Tóth and Péter Huszthy
Molecules 2021, 26(13), 4043; https://doi.org/10.3390/molecules26134043 - 1 Jul 2021
Cited by 7 | Viewed by 2499
Abstract
Acridino-diaza-20-crown-6 ether derivatives as new turn-on type fluorescent chemosensors with an excellent functionality and photophysical properties have been designed and synthesized for metal ion-selective optochemical sensing applications. Spectroscopic studies revealed that in an acetonitrile-based semi-aqueous medium, the sensor molecules exhibited a remarkable fluorescence [...] Read more.
Acridino-diaza-20-crown-6 ether derivatives as new turn-on type fluorescent chemosensors with an excellent functionality and photophysical properties have been designed and synthesized for metal ion-selective optochemical sensing applications. Spectroscopic studies revealed that in an acetonitrile-based semi-aqueous medium, the sensor molecules exhibited a remarkable fluorescence enhancement with high sensitivity only toward Zn2+, Al3+ and Bi3+, among 23 different metal ions. Studies on complexation showed a great coordinating ability of logK > 4.7 with a 1:1 complex stoichiometry in each case. The detection limits were found to be from 59 nM to micromoles. The new ionophores enabled an optical response without being affected either by the pH in the range of 5.5–7.5, or the presence of various anions or competing metal ions. Varying the N-substituents of the new host-backbone provides diverse opportunities in both immobilization and practical applications without influencing the molecular recognition abilities. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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12 pages, 3415 KiB  
Article
Stabilization of Near Identical Hydrogen Bonded Octameric Water Clusters in Crystal Structures of Three Distinct Non-Charged Polyamide Macrocyclic Host Molecules
by Kajetan Dąbrowa, Magdalena Ceborska and Janusz Jurczak
Molecules 2021, 26(9), 2787; https://doi.org/10.3390/molecules26092787 - 9 May 2021
Cited by 3 | Viewed by 2001
Abstract
In this paper, we present a comparative analysis of the solid state structures of three well-resolved hydrates of macrocyclic host molecules 1a, 1b, and 2 containing an intrannular amide-aryl substituent (lariat arm) connected to a fixed 26-membered ring in a normal [...] Read more.
In this paper, we present a comparative analysis of the solid state structures of three well-resolved hydrates of macrocyclic host molecules 1a, 1b, and 2 containing an intrannular amide-aryl substituent (lariat arm) connected to a fixed 26-membered ring in a normal (-NHCOAr, hosts 1a and 1b) or reverse manner (-CONHAr, host 2). Despite different chemical structures, these hosts crystallize as isostructural tetrahydrates in the same P-1 space group. Moreover, their crystals exhibit identical hydrogen bond motifs resulting in a stabilization of an almost identical unusual octameric water cluster built from the cyclic tetramer core and four water molecules, attached sequentially in an “up-and-down” manner. Further analysis reveals that, among the series, the structure of host 2 provides the most suitable environment for the accommodation of this type of water cluster. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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Review

Jump to: Research

19 pages, 2840 KiB  
Review
Liquid Chromatographic Enantioseparations Utilizing Chiral Stationary Phases Based on Crown Ethers and Cyclofructans
by Róbert Berkecz, Gábor Németi, Antal Péter and István Ilisz
Molecules 2021, 26(15), 4648; https://doi.org/10.3390/molecules26154648 - 31 Jul 2021
Cited by 19 | Viewed by 3221
Abstract
Natural compounds can exist in different forms, where molecules possessing chirality play an essential role in living organisms. Currently, one of the most important tasks of modern analytical chemistry is the enantioseparation of chiral compounds, in particular, the enantiomers of compounds having biological [...] Read more.
Natural compounds can exist in different forms, where molecules possessing chirality play an essential role in living organisms. Currently, one of the most important tasks of modern analytical chemistry is the enantioseparation of chiral compounds, in particular, the enantiomers of compounds having biological and/or pharmaceutical activity. Whether the task is to analyze environmental or food samples or to develop an assay for drug control, well-reproducible, highly sensitive, stereoselective, and robust methods are required. High-performance liquid chromatography best meets these conditions. Nevertheless, in many cases, gas chromatography, supercritical fluid chromatography, or capillary electrophoresis can also offer a suitable solution. Amino acids, proteins, cyclodextrins, derivatized polysaccharides, macrocyclic glycopeptides, and ion exchangers can serve as efficient selectors in liquid chromatography, and they are quite frequently applied and reviewed. Crown ethers and cyclofructans possessing similar structural characteristics and selectivity in the enantiodiscrimination of different amine compounds are discussed less frequently. This review collects information on enantioseparations achieved recently with the use of chiral stationary phases based on crown ethers or cyclofructans, focusing on liquid chromatographic applications. Full article
(This article belongs to the Special Issue Synthesis and Molecular Recognition of Macrocyclic Compounds)
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