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Pharmaceuticals
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Click Reactions in Medicinal Chemistry II
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Click Reactions in Medicinal Chemistry II

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 25 February 2025 | Viewed by 7325

Special Issue Editor

Dr. Damien Bosc

E-Mail Website
Guest Editor
Inserm—Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, Université de Lille, 59006 Lille, France
Interests: click chemistry; macrocycles; drug design; metalloproteases; KTGS; medicinal chemistry; chemical probes; chemical space; new modalities.
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the term “click chemistry” was coined by K. B. Sharpless 20 years ago, click reactions have been used for their wide range of assets by medicinal chemists. In recognition of the tremendous impact of click chemistry, the Royal Swedish Academy of Sciences awarded the Nobel Prize in Chemistry 2022 to Dr. Carolyn R. Bertozzi, Dr. Morten Meldal, and Dr. K. Barry Sharpless. These “click chemistry” reactions share many features such as a high yield, modularity, large scope, and stereospecificity, which meet the requirements of drug discovery. Indeed, this field is in constant search of methodologies that allow for fast and easy access to large libraries of compounds. The ability to carry out click reactions in biological media is of great interest to medicinal chemists who wish to perform chemistry with biological macromolecules.

The flagship of click chemistry reactions, copper-catalyzed azide-alkyne cycloaddition (CuAAC), has all of these advantages. Moreover, the resulting 1,4-disubstituted 1,2,3-triazoles exhibit favorable physicochemical properties, which are particularly appealing for medicinal chemists. In addition to CuAAC, other click reactions are exploited for drug discovery, such as cycloadditions involving various reactants (e.g., mesoionics, isocyanides, and alkenes), nucleophilic substitutions on three-membered heterocycles (epoxides and aziridines), and addition reactions with carbon–carbon multiple bonds or a sulfur–fluoride exchange (SuFEx).

The applications of click reactions in medicinal chemistry are numerous. Almost all facets of drug discovery are involved. For example, bioorthogonal click reactions are convenient for designing chemical probes for target validation and proteomics. Hits can then be identified by screening large libraries that stem from diversity-oriented click synthesis or through in situ protein-templated click chemistry. Click reactions are also useful for lead optimization when considering bioisosterism, pharmacophore, linking, and ADME.

For this Special Issue, comprehensive reviews, original research articles, and short communications highlighting the potential of click reactions in medicinal chemistry and focusing on, but not limited to, the synthesis of privileged scaffolds, and the design and optimization of small molecules or new modalities (macrocycles and PROTACs) for therapeutic applications and proteomics, are welcome.

Dr. Damien Bosc
Guest Editor

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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • click chemistry
  • drug discovery
  • chemical probes
  • bioorthogonal reactions
  • protein-templated reactions
  • bioisosteres
  • bioconjugation
  • cycloaddition
  • 1,2,3-triazole
  • chemical space

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Published Papers (4 papers)

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Research

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12 pages, 638 KiB  
Article
Exploring Benzo[h]chromene Derivatives as Agents against Protozoal and Mycobacterial Infections
by Mariano Walter Pertino, Alexander F. de la Torre, Guillermo Schmeda-Hirschmann, Celeste Vega Gómez, Miriam Rolón, Cathia Coronel, Antonieta Rojas de Arias, Carmen A. Molina-Torres, Lucio Vera-Cabrera and Ezequiel Viveros-Valdez
Pharmaceuticals 2024, 17(10), 1375; https://doi.org/10.3390/ph17101375 - 16 Oct 2024
Viewed by 617
Abstract
Background/Objectives: In this study, the efficacy of benzo[h]chromene derivatives as antiprotozoal and antimycobacterial agents was explored. Methods: A total of twenty compounds, including benzo[h]chromene alkyl diesters and benzo[h]chromene-triazole derivatives, were synthesized and tested against Trypanosoma cruzi, Leishmania braziliensis, L. infantum, [...] Read more.
Background/Objectives: In this study, the efficacy of benzo[h]chromene derivatives as antiprotozoal and antimycobacterial agents was explored. Methods: A total of twenty compounds, including benzo[h]chromene alkyl diesters and benzo[h]chromene-triazole derivatives, were synthesized and tested against Trypanosoma cruzi, Leishmania braziliensis, L. infantum, and strains of Mycobacterium abscessus and Mycobacterium intracellulare LIID-01. Notably, compounds 1a, 1b, 2a, and 3f exhibited superior activity against Trypanosoma cruzi, with IC50 values of 19.2, 37.3, 68.7, and 24.7 µM, respectively, outperforming the reference drug benznidazole (IC50: 54.7 µM). Results: Compounds 1b and 3f showed excellent selectivity indices against Leishmania braziliensis, with SI values of 19 and 18, respectively, suggesting they could be potential alternatives to the commonly used, but more selective, miltefosine (IC50: 64.0 µM, SI: 43.0). Additionally, compounds 1a, 1b, and 3f were most effective against Leishmania infantum, with IC50 values of 24.9, 30.5, and 46.6 µM, respectively. Compounds 3f and 3h were particularly potent against various Mycobacterium abscessus strains, highlighting their significance given the inherent resistance of these bacteria to standard antimicrobials. Conclusions: The sensitivity of Mycobacterium intracellulare LIID-01 to these compounds also underscored their potential in managing infections by the Mycobacterium avium–intracellulare complex. Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry II)
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17 pages, 3737 KiB  
Article
Synthesis of a [18F]F Estradiol Derivative via Click Chemistry Using an Automated Synthesis Module: In Vitro Evaluation as Potential Radiopharmaceutical for Breast Cancer Imaging
by María Emilia Tejería, María Pía Pereira, Juan Pablo Gambini, Pablo Duarte, Javier Gabriel Giglio and Ana María Rey
Pharmaceuticals 2024, 17(3), 388; https://doi.org/10.3390/ph17030388 - 18 Mar 2024
Cited by 1 | Viewed by 1361
Abstract
“Click reactions” are a very useful tool for the selective conjugation of different molecular subunits to produce complex structures in a simple way. In this paper, we present the application of Cu(I)-catalyzed biorthogonal reactions between alkynes and azides to the indirect radiofluorination of [...] Read more.
“Click reactions” are a very useful tool for the selective conjugation of different molecular subunits to produce complex structures in a simple way. In this paper, we present the application of Cu(I)-catalyzed biorthogonal reactions between alkynes and azides to the indirect radiofluorination of an estradiol derivative with potential applications in estrogen receptor imaging. The procedure was fully developed on an automated synthesis platform, and conditions were optimized to achieve the desired product with a reasonable yield without precipitation. Although the biological results were not adequate for a potential radiopharmaceutical, the outcome of this work is valuable since the use of automated platforms is required for the reliable and reproducible preparation of PET radiopharmaceuticals in GMP conditions while limiting the radiation dose rates to the personnel. Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry II)
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15 pages, 5242 KiB  
Article
Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions
by Matt Timmers, Andi Kipper, Raphael Frey, Stef Notermans, Maksym Voievudskyi, Claire Wilson, Nina Hentzen, Michael Ringle, Clara Bovino, Bernhard Stump, Cristianne J. F. Rijcken, Tina Vermonden, Ingrid Dijkgraaf and Rob Liskamp
Pharmaceuticals 2023, 16(8), 1155; https://doi.org/10.3390/ph16081155 - 15 Aug 2023
Cited by 1 | Viewed by 3278
Abstract
The recently developed compound, tetramethylthiocycloheptyne sulfoximine (TMTHSI), has shown to be a promising strained alkyne for strain-promoted azide–alkyne cycloaddition (SPAAC), metal-free click chemistry. This research explores the properties of TMTHSI-based compounds via three aspects: (1) large-scale production, (2) unique stability in acidic conditions [...] Read more.
The recently developed compound, tetramethylthiocycloheptyne sulfoximine (TMTHSI), has shown to be a promising strained alkyne for strain-promoted azide–alkyne cycloaddition (SPAAC), metal-free click chemistry. This research explores the properties of TMTHSI-based compounds via three aspects: (1) large-scale production, (2) unique stability in acidic conditions and its subsequent use in peptide synthesis, and (3) the functionalization of antibodies. Here, it is shown that (1) scale-up is achieved on a scale of up to 100 g. (2) TMTHSI is remarkably stable against TFA allowing for the site-specific functionalization of peptides on resin. Finally, (3) the functionalization of an antibody with a model payload is very efficient, with antibody conjugation demonstrating more beneficial features such as a high yield and limited hydrophobicity as compared to other alkyne reagent conjugates. These results illustrate the high potential of TMTHSI for diverse bioconjugation applications, with production already being GMP-compatible and a highly efficient conversion resulting in attractive costs of goods. Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry II)
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Review

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16 pages, 22881 KiB  
Review
Click Chemistry in Polymersome Technology
by Nuno M. Saraiva, Ana Alves, Paulo C. Costa and Marta Correia-da-Silva
Pharmaceuticals 2024, 17(6), 747; https://doi.org/10.3390/ph17060747 - 6 Jun 2024
Cited by 1 | Viewed by 1291
Abstract
Polymersomes, self-assembled nanoparticles composed of amphiphilic block copolymers, have emerged as promising versatile nanovesicles with various applications, such as drug delivery, medical imaging, and diagnostics. The integration of click chemistry reactions, specifically the copper [I]-catalysed azide–alkyne cycloaddition (CuAAC), has greatly expanded the functionalisation [...] Read more.
Polymersomes, self-assembled nanoparticles composed of amphiphilic block copolymers, have emerged as promising versatile nanovesicles with various applications, such as drug delivery, medical imaging, and diagnostics. The integration of click chemistry reactions, specifically the copper [I]-catalysed azide–alkyne cycloaddition (CuAAC), has greatly expanded the functionalisation and bioconjugation capabilities of polymersomes and new drugs, being this synergistic combination explored in this review. It also provides up-to-date examples of previous incorporations of click-compatible moieties (azide and alkyne functional groups) into polymer building blocks, enabling the “click” attachment of various functional groups and ligands, delving into the diverse range of click reactions that have been reported and employed for polymersome copolymer synthesis and the modification of polymersome surfaces, including ligand conjugation and surface modification. Overall, this review explores the current state-of-the-art of the combinatory usage, in recent years, of polymersomes with the click chemistry reaction, highlighting examples of studies of their synthesis and functionalisation strategies. Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry II)
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