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Design and Synthesis of Bioactive Organic Molecules

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

Deadline for manuscript submissions: closed (30 May 2023) | Viewed by 9124

Special Issue Editor


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Guest Editor
Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, SE-106 91, 114 18 Solna, Sweden
Interests: organic synthesis; retrosynthesis; heterocycles; natural products; total synthesis; small organic molecules; drug discovery

Special Issue Information

Dear Colleagues,

Ever since ancient times small organic molecules have constituted an important role as remedies for various diseases. The tremendous development in the area of synthetic organic chemistry the last century have provided the contemporary organic chemists with an increased toolbox of synthetic transformations possible in the lab. Both to make new compounds and to refine the routes of already existing ones. The aim of this special issue “Design and synthesis of bioactive organic molecules” is to provide the readers with recent examples of syntheses of bioactive organic molecules. Regardless of biological target, large or small, natural or synthetic compounds, chiral or not, small or large scale, with an emphasis on the synthetic chemistry.

Dr. Christoffer Bengtsson
Guest Editor

Manuscript Submission Information

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Keywords

  • organic synthesis
  • retrosynthesis
  • heterocycles
  • natural products
  • total synthesis
  • small organic molecules
  • drug discovery

Published Papers (7 papers)

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Research

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13 pages, 2232 KiB  
Article
Polyaromatic Bis(indolyl)methane Derivatives with Antiproliferative and Antiparasitic Activity
by Raquel C. R. Gonçalves, Pablo Peñalver, Susana P. G. Costa, Juan C. Morales and Maria Manuela M. Raposo
Molecules 2023, 28(23), 7728; https://doi.org/10.3390/molecules28237728 - 23 Nov 2023
Viewed by 830
Abstract
Bis(indolyl)methanes (BIMs) are a class of compounds that have been recognized as an important core in the design of drugs with important pharmacological properties, such as promising anticancer and antiparasitic activities. Here, we explored the biological activity of the BIM core functionalized [...] Read more.
Bis(indolyl)methanes (BIMs) are a class of compounds that have been recognized as an important core in the design of drugs with important pharmacological properties, such as promising anticancer and antiparasitic activities. Here, we explored the biological activity of the BIM core functionalized with different (hetero)aromatic moieties. We synthesized substituted BIM derivatives with triphenylamine, N,N-dimethyl-1-naphthylamine and 8-hydroxylquinolyl groups, studied their photophysical properties and evaluated their in vitro antiproliferative and antiparasitic activities. The triphenylamine BIM derivative 2a displayed an IC50 of 3.21, 3.30 and 3.93 μM against Trypanosoma brucei, Leishmania major and HT-29 cancer cell line, respectively. The selectivity index demonstrated that compound 2a was up to eight-fold more active against the parasites and HT-29 than against the healthy cell line MRC-5. Fluorescence microscopy studies with MRC-5 cells and T. brucei parasites incubated with derivative 2a indicate that the compound seems to accumulate in the cell’s mitochondria and in the parasite’s nucleus. In conclusion, the BIM scaffold functionalized with the triphenylamine moiety proved to be the most promising antiparasitic and anticancer agent of this series. Full article
(This article belongs to the Special Issue Design and Synthesis of Bioactive Organic Molecules)
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15 pages, 5684 KiB  
Article
Synthesis of Azuleno[2,1-b]quinolones and Quinolines via Brønsted Acid-Catalyzed Cyclization of 2-Arylaminoazulenes
by Taku Shoji, Mutsumi Takeuchi, Mayumi Uda, Yukino Ariga, Akari Yamazaki, Ryuta Sekiguchi and Shunji Ito
Molecules 2023, 28(15), 5785; https://doi.org/10.3390/molecules28155785 - 31 Jul 2023
Viewed by 917
Abstract
Quinolone and quinoline derivatives are frequently found as substructures in pharmaceutically active compounds. In this paper, we describe a procedure for the synthesis of azuleno[2,1-b]quinolones and quinolines from 2-arylaminoazulene derivatives, which are readily prepared via the aromatic nucleophilic substitution reaction of [...] Read more.
Quinolone and quinoline derivatives are frequently found as substructures in pharmaceutically active compounds. In this paper, we describe a procedure for the synthesis of azuleno[2,1-b]quinolones and quinolines from 2-arylaminoazulene derivatives, which are readily prepared via the aromatic nucleophilic substitution reaction of a 2-chloroazulene derivative with several arylamines. The synthesis of azuleno[2,1-b]quinolones was established by the Brønsted acid-catalyzed intramolecular cyclization of 2-arylaminoazulene derivatives bearing two ester groups at the five-membered ring. The halogenative aromatization of azuleno[2,1-b]quinolones with POCl3 yielded azuleno[2,1-b]quinolines with a chlorine substituent at the pyridine moiety. The aromatic nucleophilic substitution reaction of azuleno[2,1-b]quinolines bearing chlorine substituent with secondary amines was also investigated to afford the aminoquinoline derivatives. These synthetic methodologies reported in this paper should be valuable in the development of new pharmaceuticals based on the azulene skeleton. Full article
(This article belongs to the Special Issue Design and Synthesis of Bioactive Organic Molecules)
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9 pages, 1455 KiB  
Communication
Three-Step Synthesis of the Antiepileptic Drug Candidate Pynegabine
by Yi-Jing Sun, Ya-Ling Gong, Shi-Chao Lu, Shi-Peng Zhang and Shu Xu
Molecules 2023, 28(13), 4888; https://doi.org/10.3390/molecules28134888 - 21 Jun 2023
Viewed by 1062
Abstract
Pynegabine, an antiepileptic drug candidate in phase I clinical trials, is a structural analog of the marketed drug retigabine with improved chemical stability, strong efficacy, and a better safety margin. The reported shortest synthetic route for pynegabine contains six steps and involves the [...] Read more.
Pynegabine, an antiepileptic drug candidate in phase I clinical trials, is a structural analog of the marketed drug retigabine with improved chemical stability, strong efficacy, and a better safety margin. The reported shortest synthetic route for pynegabine contains six steps and involves the manipulation of highly toxic methyl chloroformate and dangerous hydrogen gas. To improve the feasibility of drug production, we developed a concise, three-step process using unconventional methoxycarbonylation and highly efficient Buchwald–Hartwig cross coupling. The new synthetic route generated pynegabine at the decagram scale without column chromatographic purification and avoided the dangerous manipulation of hazardous reagents. Full article
(This article belongs to the Special Issue Design and Synthesis of Bioactive Organic Molecules)
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7 pages, 1282 KiB  
Communication
Rapid Construction of a Chloromethyl-Substituted Duocarmycin-like Prodrug
by Christoffer Bengtsson and Ylva Gravenfors
Molecules 2023, 28(12), 4818; https://doi.org/10.3390/molecules28124818 - 16 Jun 2023
Viewed by 833
Abstract
The construction of duocarmycin-like compounds is often associated with lengthy synthetic routes. Presented herein is the development of a short and convenient synthesis of a type of duocarmycin prodrug. The 1,2,3,6-tetrahydropyrrolo[3,2-e]indole-containing core is here constructed from commercially available Boc-5-bromoindole in four [...] Read more.
The construction of duocarmycin-like compounds is often associated with lengthy synthetic routes. Presented herein is the development of a short and convenient synthesis of a type of duocarmycin prodrug. The 1,2,3,6-tetrahydropyrrolo[3,2-e]indole-containing core is here constructed from commercially available Boc-5-bromoindole in four steps and 23% overall yield, utilizing a Buchwald–Hartwig amination followed by a sodium hydride-induced regioselective bromination. In addition, protocols for selective mono- and di-halogenations of positions 3 and 4 were also developed, which could be useful for further exploration of this scaffold. Full article
(This article belongs to the Special Issue Design and Synthesis of Bioactive Organic Molecules)
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18 pages, 2875 KiB  
Article
Sustainable Synthesis, Antiproliferative and Acetylcholinesterase Inhibition of 1,4- and 1,2-Naphthoquinone Derivatives
by Rafaela G. Cabral, Gonçalo Viegas, Rita Pacheco, Ana Catarina Sousa and Maria Paula Robalo
Molecules 2023, 28(3), 1232; https://doi.org/10.3390/molecules28031232 - 27 Jan 2023
Cited by 1 | Viewed by 1627
Abstract
This work describes the design, sustainable synthesis, evaluation of electrochemical and biological properties against HepG2 cell lines, and AChE enzymes of different substituted derivatives of 1,4- and 1,2-naphthoquinones (NQ). A microwave-assisted protocol was optimized with success for the synthesis of the 2-substituted-1,4-NQ series [...] Read more.
This work describes the design, sustainable synthesis, evaluation of electrochemical and biological properties against HepG2 cell lines, and AChE enzymes of different substituted derivatives of 1,4- and 1,2-naphthoquinones (NQ). A microwave-assisted protocol was optimized with success for the synthesis of the 2-substituted-1,4-NQ series and extended to the 4-substituted-1,2-NQ family, providing an alternative and more sustainable approach to the synthesis of naphthoquinones. The electrochemical properties were studied by cyclic voltammetry, and the redox potentials related to the molecular structural characteristics and the biological properties. Compounds were tested for their potential anti-cancer activity against a hepatocellular carcinoma cell line, HepG2, using MTT assay, and 1,2-NQ derivatives were found to be more active than their 1,4-NQ homologues (3af), with the highest cytotoxic potential found for compound 4a (EC50 = 3 μM). The same trend was found for the inhibitory action against acetylcholinesterase, with 1,2-NQ derivatives showing higher inhibition50µM than their 1,4-NQ homologues, with 4h being the most potent compound (Inhibition50µM = 85%). Docking studies were performed for the 1,2-NQ derivatives with the highest inhibitions, showing dual binding interactions with both CAS and PAS sites, while the less active 1,4-NQ derivatives showed interactions with PAS and the mid-gorge region. Full article
(This article belongs to the Special Issue Design and Synthesis of Bioactive Organic Molecules)
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21 pages, 10565 KiB  
Article
Novel Nanomolar Allosteric Modulators of AMPA Receptor of Bis(pyrimidine) Series: Synthesis, Biotesting and SAR Analysis
by Kseniya N. Sedenkova, Denis V. Zverev, Anna A. Nazarova, Mstislav I. Lavrov, Eugene V. Radchenko, Yuri K. Grishin, Alexey V. Gabrel’yan, Vladimir L. Zamoyski, Vladimir V. Grigoriev, Elena B. Averina and Vladimir A. Palyulin
Molecules 2022, 27(23), 8252; https://doi.org/10.3390/molecules27238252 - 26 Nov 2022
Cited by 4 | Viewed by 1313
Abstract
Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative disorders. Dimeric molecules have been reported to have an especially potent modulating effect, due to the U-shaped form of the AMPA [...] Read more.
Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative disorders. Dimeric molecules have been reported to have an especially potent modulating effect, due to the U-shaped form of the AMPA receptor’s allosteric binding site. In the present work, novel bis(pyrimidines) were studied as AMPA receptor modulators. A convenient and flexible preparative approach to bis(pyrimidines) containing a hydroquinone linker was elaborated, and a series of derivatives with varied substituents was obtained. The compounds were examined in the patch clamp experiments for their influence on the kainate-induced currents, and 10 of them were found to have potentiating properties. The best potency was found for 2-methyl-4-(4-((2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)oxy)phenoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine, which potentiated the kainate-induced currents by up to 77% in all tested concentrations (10−12–10−6 M). The results were rationalized via the modeling of modulator complexes with the dimeric ligand binding domain of the GluA2 AMPA receptor, using molecular docking and molecular dynamics simulation. The prediction of ADMET, physicochemical, and PAINS properties of the studied bis(pyrimidines) confirmed that PAMs of this type may act as the potential lead compounds for the development of neuroprotective drugs. Full article
(This article belongs to the Special Issue Design and Synthesis of Bioactive Organic Molecules)
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Review

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23 pages, 9984 KiB  
Review
Synthetic Studies on Tetracyclic Diquinane Lycopodium Alkaloids Magellanine, Magellaninone and Paniculatine
by Takeru Saito, John Mark Awad and Wei Zhang
Molecules 2023, 28(3), 1501; https://doi.org/10.3390/molecules28031501 - 03 Feb 2023
Viewed by 1725
Abstract
(–)-Magellanine, (+)-magellaninone, and (+)-paniculatine are three natural products isolated from the Lycopodium family that share a unique 6-5-5-6-fused tetracyclic diquinane core skeleton. Several members of this family have potent s anti-inflammatory and acetylcholinesterase-inhibitory properties and are under development for the treatment of Alzheimer’s [...] Read more.
(–)-Magellanine, (+)-magellaninone, and (+)-paniculatine are three natural products isolated from the Lycopodium family that share a unique 6-5-5-6-fused tetracyclic diquinane core skeleton. Several members of this family have potent s anti-inflammatory and acetylcholinesterase-inhibitory properties and are under development for the treatment of Alzheimer’s and other neurodegenerative diseases. Several research groups have undertaken the formal and total syntheses of this class of natural products. This review highlights over 20 reported total syntheses of these three alkaloids and the development of synthetic methods for the assembly of their core skeletons. Full article
(This article belongs to the Special Issue Design and Synthesis of Bioactive Organic Molecules)
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