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Bioorganic Chemistry in Europe: When Organic Chemistry Meets Molecular Biology
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Bioorganic Chemistry in Europe: When Organic Chemistry Meets Molecular Biology

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

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 16265

Special Issue Editors

Prof. Dr. Jadwiga Handzlik

E-Mail Website
Guest Editor
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
Interests: medicinal chemistry; synthesis; CADD; multidrug resistance; memory disorders; depression; Alzheimer’s disease; arrhythmia; ADMET; imidazolone; hydantoin; thiohydantoin; piperazine; selenium; chalcogen
Special Issues, Collections and Topics in MDPI journals
Dr. Katarzyna Kucwaj-Brysz

E-Mail Website
Guest Editor
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University in Cracow, Medyczna 9, PL 30-688 Cracow, Poland
Interests: medicinal chemistry; organic chemistry; GPCR’s ligands; CNS agents; anticancer agents; computer-aided drug design

Special Issue Information

Dear Colleagues,

Bioorganic chemistry is a fascinating field where chemistry meets biology. It includes studies on a broad spectrum of chemical structures, from low molecular weight agents and natural products to macromolecules, such as proteins and nucleic acids. The investigation of chemistry–biology interplay very often provides an understanding of physiological processes and may lead to an identification of the strategies for the development of innovative therapies for unmet clinical needs. Computer-aided approaches thus become an inseparable third partner of experimental organic chemistry and molecular biology to solve all mechanistic mysteries at the molecular level.

The vast majority of bioactive organic compounds contain heterocycles in their structures. One of the main reasons for this is the fact that the introduction of nitrogen and/or chalcogens may significantly influence both biological activity and psychochemical properties (e.g., solubility, lipophilicity, hydrogen bonding capacity).            

We kindly invite to this Special Issue researchers from different parts of Europe, whose “regionally representative” studies are focused on dealing with biological challenges using heterocycle-containing organic compounds. Various computer-aided studies that enrich knowledge about molecular mechanisms of biological effects are desirable, too.

Full research articles, short communications, as well as comprehensive reviews are welcome. 

Prof. Dr. Jadwiga Handzlik
Dr. Katarzyna Kucwaj-Brysz
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Heterocycles 
  • Organic synthesis 
  • Bioactive compounds
  • Drug discovery 
  • Novel therapeutic targets 
  • Molecular modeling 
  • Innovative therapies

Published Papers (7 papers)

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Research

26 pages, 13734 KiB  
Article
Discovery of a Novel Chemo-Type for TAAR1 Agonism via Molecular Modeling
by Giancarlo Grossi, Naomi Scarano, Francesca Musumeci, Michele Tonelli, Evgeny Kanov, Anna Carbone, Paola Fossa, Raul R. Gainetdinov, Elena Cichero and Silvia Schenone
Molecules 2024, 29(8), 1739; https://doi.org/10.3390/molecules29081739 - 11 Apr 2024
Viewed by 287
Abstract
The search for novel effective TAAR1 ligands continues to draw great attention due to the wide range of pharmacological applications related to TAAR1 targeting. Herein, molecular docking studies of known TAAR1 ligands, characterized by an oxazoline core, have been performed in order to [...] Read more.
The search for novel effective TAAR1 ligands continues to draw great attention due to the wide range of pharmacological applications related to TAAR1 targeting. Herein, molecular docking studies of known TAAR1 ligands, characterized by an oxazoline core, have been performed in order to identify novel promising chemo-types for the discovery of more active TAAR1 agonists. In particular, the oxazoline-based compound S18616 has been taken as a reference compound for the computational study, leading to the development of quite flat and conformationally locked ligands. The choice of a “Y-shape” conformation was suggested for the design of TAAR1 ligands, interacting with the protein cavity delimited by ASP103 and aromatic residues such as PHE186, PHE195, PHE268, and PHE267. The obtained results allowed us to preliminary in silico screen an in-house series of pyrimidinone-benzimidazoles (1a–10a) as a novel scaffold to target TAAR1. Combined ligand-based (LBCM) and structure based (SBCM) computational methods suggested the biological evaluation of compounds 1a–10a, leading to the identification of derivatives 1a–3a (hTAAR1 EC50 = 526.3–657.4 nM) as promising novel TAAR1 agonists. Full article
(This article belongs to the Special Issue Bioorganic Chemistry in Europe: When Organic Chemistry Meets Molecular Biology)
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19 pages, 22447 KiB  
Article
Structural Modeling of TRPA1 Ion Channel—Determination of the Binding Site for Antagonists
by Alicja Gawalska, Marcin Kołaczkowski and Adam Bucki
Molecules 2022, 27(10), 3077; https://doi.org/10.3390/molecules27103077 - 11 May 2022
Cited by 4 | Viewed by 2691
Abstract
TRPA1 is a transmembrane cation channel, one of the most promising targets in the context of respiratory diseases. Its general structure has already been experimentally resolved, but the binding site of TRPA1 antagonists such as HC-030031, a model methylxanthine derivative, remains unknown. The [...] Read more.
TRPA1 is a transmembrane cation channel, one of the most promising targets in the context of respiratory diseases. Its general structure has already been experimentally resolved, but the binding site of TRPA1 antagonists such as HC-030031, a model methylxanthine derivative, remains unknown. The present study aimed to determine the potential binding site of xanthine antagonists and to describe their binding mode, using a molecular modeling approach. This study represents the first attempt to bring together site-directed mutagenesis reports and the latest cryo-EM structure of an antagonist bound to TRPA1. Our research suggests that the core moiety of HC-030031 binds to a pocket formed by the TRP-like domain and the pre-S1, S4, S5 helices of one subunit. The structure, determined by cryo-EM, shows interactions of a core hypoxanthine moiety in the same area of the binding site, sharing the interaction of xanthine/hypoxanthine with Trp-711. Moreover, the predicted binding mode of HC-030031 assumes interaction with Asn-855, a residue demonstrated to be important for HC-030031 recognition in site-directed mutagenesis studies. Our model proved to be advantageous in a retrospective virtual screening benchmark; therefore, it will be useful in research on new TRPA1 antagonists among xanthine derivatives and their bioisosteres. Full article
(This article belongs to the Special Issue Bioorganic Chemistry in Europe: When Organic Chemistry Meets Molecular Biology)
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20 pages, 6511 KiB  
Article
Coumarin-Resveratrol-Inspired Hybrids as Monoamine Oxidase B Inhibitors: 3-Phenylcoumarin versus trans-6-Styrylcoumarin
by Marco Mellado, César González, Jaime Mella, Luis F. Aguilar, Ismail Celik, Fernanda Borges, Eugenio Uriarte, Giovanna Delogu, Dolores Viña and Maria J. Matos
Molecules 2022, 27(3), 928; https://doi.org/10.3390/molecules27030928 - 29 Jan 2022
Cited by 13 | Viewed by 2471
Abstract
Monoamine oxidases (MAOs) are attractive targets in drug design. The inhibition of one of the isoforms (A or B) is responsible for modulating the levels of different neurotransmitters in the central nervous system, as well as the production of reactive oxygen species. Molecules [...] Read more.
Monoamine oxidases (MAOs) are attractive targets in drug design. The inhibition of one of the isoforms (A or B) is responsible for modulating the levels of different neurotransmitters in the central nervous system, as well as the production of reactive oxygen species. Molecules that act selectively on one of the MAO isoforms have been studied deeply, and coumarin has been described as a promising scaffold. In the current manuscript we describe a comparative study between 3-phenylcoumarin (endo coumarin-resveratrol-inspired hybrid) and trans-6-styrylcoumarin (exo coumarin-resveratrol-inspired hybrid). Crystallographic structures of both compounds were obtained and analyzed. 3D-QSAR models, in particular CoMFA and CoMSIA, docking simulations and molecular dynamics simulations have been performed to support and better understand the interaction of these molecules with both MAO isoforms. Both molecules proved to inhibit MAO-B, with trans-6-styrylcoumarin being 107 times more active than 3-phenylcoumarin, and 267 times more active than trans-resveratrol. Full article
(This article belongs to the Special Issue Bioorganic Chemistry in Europe: When Organic Chemistry Meets Molecular Biology)
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19 pages, 2352 KiB  
Article
Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies
by Gniewomir Latacz, Kinga Sałat, Anna Furgała-Wojas, Adrian Martyniak, Agnieszka Olejarz-Maciej, Ewelina Honkisz-Orzechowska and Ewa Szymańska
Molecules 2022, 27(3), 875; https://doi.org/10.3390/molecules27030875 - 27 Jan 2022
Cited by 4 | Viewed by 2313
Abstract
Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power [...] Read more.
Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity fluorescent (ORAC-FL) assays. The most active antioxidants 1 and 8 were further examined to evaluate their neuroprotective properties in vitro. In this study, compound 1 showed a significant neuroprotective effect against the neurotoxin 6-hydroxydopamine in neuroblastoma SH-SY5Y and IMR-32 cell lines. Both compounds also showed prevention from high levels of reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, the desired monoamine oxidase B (MAO-B) inhibition effect (IC50 = 278 ± 29 nM) for 1 was determined. No toxic effects up to 100 µM of 1 and 8 against neuroblastoma cells were observed. Furthermore, in vivo studies showed that compound 1 demonstrated significant anticonvulsant potential in 6-Hz test, but in neuropathic pain models its antiallodynic and antihyperalgesic properties were not observed. Concluding, the compound 1 seems to be of higher importance as a new phenylalanine-based lead candidate due to its confirmed promise in in vitro and in vivo anticonvulsant activity. Full article
(This article belongs to the Special Issue Bioorganic Chemistry in Europe: When Organic Chemistry Meets Molecular Biology)
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16 pages, 5691 KiB  
Article
The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives
by Katarzyna Kucwaj-Brysz, Anna Dela, Sabina Podlewska, Marek Bednarski, Agata Siwek, Grzegorz Satała, Kinga Czarnota, Jadwiga Handzlik and Katarzyna Kieć-Kononowicz
Molecules 2021, 26(22), 7025; https://doi.org/10.3390/molecules26227025 - 20 Nov 2021
Cited by 4 | Viewed by 1886
Abstract
Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents [...] Read more.
Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α1A/α1D affinity and selectivity towards α1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents. Full article
(This article belongs to the Special Issue Bioorganic Chemistry in Europe: When Organic Chemistry Meets Molecular Biology)
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16 pages, 4623 KiB  
Article
Comparison of Nonheme Manganese- and Iron-Containing Flavone Synthase Mimics
by Dóra Lakk-Bogáth, Natalija Pantalon Juraj, Bashdar I. Meena, Berislav Perić, Srećko I. Kirin and József Kaizer
Molecules 2021, 26(11), 3220; https://doi.org/10.3390/molecules26113220 - 27 May 2021
Cited by 5 | Viewed by 2571
Abstract
Heme and nonheme-type flavone synthase enzymes, FS I and FS II are responsible for the synthesis of flavones, which play an important role in various biological processes, and have a wide range of biomedicinal properties including antitumor, antimalarial, and antioxidant activities. To get [...] Read more.
Heme and nonheme-type flavone synthase enzymes, FS I and FS II are responsible for the synthesis of flavones, which play an important role in various biological processes, and have a wide range of biomedicinal properties including antitumor, antimalarial, and antioxidant activities. To get more insight into the mechanism of this curious enzyme reaction, nonheme structural and functional models were carried out by the use of mononuclear iron, [FeII(CDA-BPA*)]2+ (6) [CDA-BPA = N,N,N’,N’-tetrakis-(2-pyridylmethyl)-cyclohexanediamine], [FeII(CDA-BQA*)]2+ (5) [CDA-BQA = N,N,N’,N’-tetrakis-(2-quinolilmethyl)-cyclohexanediamine], [FeII(Bn-TPEN)(CH3CN)]2+ (3) [Bn-TPEN = N-benzyl-N,N’,N’-tris(2-pyridylmethyl)-1,2-diaminoethane], [FeIV(O)(Bn-TPEN)]2+ (9), and manganese, [MnII(N4Py*)(CH3CN)]2+ (2) [N4Py* = N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)ethylamine)], [MnII(Bn-TPEN)(CH3CN)]2+ (4) complexes as catalysts, where the possible reactive intermediates, high-valent FeIV(O) and MnIV(O) are known and well characterised. The results of the catalytic and stoichiometric reactions showed that the ligand framework and the nature of the metal cofactor significantly influenced the reactivity of the catalyst and its intermediate. Comparing the reactions of [FeIV(O)(Bn-TPEN)]2+ (9) and [MnIV(O)(Bn-TPEN)]2+ (10) towards flavanone under the same conditions, a 3.5-fold difference in reaction rate was observed in favor of iron, and this value is three orders of magnitude higher than was observed for the previously published [FeIV(O)(N2Py2Q*)]2+ [N,N-bis(2-quinolylmethyl)-1,2-di(2-pyridyl)ethylamine] species. Full article
(This article belongs to the Special Issue Bioorganic Chemistry in Europe: When Organic Chemistry Meets Molecular Biology)
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15 pages, 7302 KiB  
Article
Synthesis and Anticancer Activity Evaluation of 5-[2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-thiazolidinones
by Kamila Buzun, Anna Kryshchyshyn-Dylevych, Julia Senkiv, Olexandra Roman, Andrzej Gzella, Krzysztof Bielawski, Anna Bielawska and Roman Lesyk
Molecules 2021, 26(10), 3057; https://doi.org/10.3390/molecules26103057 - 20 May 2021
Cited by 13 | Viewed by 2558
Abstract
A series of novel 5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-thiazolidinones (Ciminalum–thiazolidinone hybrid molecules) have been synthesized. Anticancer activity screening toward the NCI60 cell lines panel, gastric cancer (AGS), human colon cancer (DLD-1), and breast cancer (MCF-7 and MDA-MB-231) cell lines allowed the identification of [...] Read more.
A series of novel 5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-thiazolidinones (Ciminalum–thiazolidinone hybrid molecules) have been synthesized. Anticancer activity screening toward the NCI60 cell lines panel, gastric cancer (AGS), human colon cancer (DLD-1), and breast cancer (MCF-7 and MDA-MB-231) cell lines allowed the identification of 3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid (2h) with the highest level of antimitotic activity with mean GI50/TGI values of 1.57/13.3 μM and a certain sensitivity profile against leukemia (MOLT-4, SR), colon cancer (SW-620), CNS cancer (SF-539), melanoma (SK-MEL-5), gastric cancer (AGS), human colon cancer (DLD-1), and breast cancers (MCF-7 and MDA-MB-231) cell lines. The hit compounds 2f, 2i, 2j, and 2h have been found to have low toxicity toward normal human blood lymphocytes and a fairly wide therapeutic range. The significant role of the 2-chloro-3-(4-nitrophenyl)prop-2-enylidene (Ciminalum) substituent in the 5 position and the substituent’s nature in the position 3 of core heterocycle in the anticancer cytotoxicity levels of 4-thiazolidinone derivatives have been established Full article
(This article belongs to the Special Issue Bioorganic Chemistry in Europe: When Organic Chemistry Meets Molecular Biology)
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