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Heterocyclic Compounds: Synthesis, Design, and Biological Activity
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Heterocyclic Compounds: Synthesis, Design, and Biological Activity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2025) | Viewed by 3561

Special Issue Editor

Prof. Dr. Josef Jampilek

E-Mail Website
Guest Editor
1. Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 84215 Bratislava, Slovakia
2. Department of Chemical Biology, Faculty of Science, Palacky University, Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic
Interests: medicinal chemistry; drug design; structure–activity relationships; pharmaceutical analysis; polymorphism; drug bioavailability; ADME; nanoparticles; nanoformulations; controlled/targeted delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although organic compounds consist of a carbon–hydrogen backbone, heteroatoms provide specificity to this skeleton. It does not matter whether these are classical heteroatoms, such as nitrogen, oxygen, or sulfur; rarer ones, such as phosphorus and selenium; or the various, widely occurring halogen groups. Isosteric/bioisosteric replacement of hydrocarbon fragments by heteroatoms can be carried out both in aliphatic structures and, much more often, in a variety of cyclic systems. Many heterocyclic structures can be considered privileged scaffolds. Heterocycles thus undoubtedly form the basis of any bioactive compounds; according to statistics, more than 85% of all biologically active chemical entities contain a heterocycle. This fact reflects the central role of heterocycles in the modern design of not only drugs but also, for example, agrochemicals. Although there are countless synthetic approaches to the preparation of heterocycles, it should also be mentioned that many heterocyclic agents have been isolated from natural sources. The type, amount, and position of heteroatoms affect not only the chemical and physical properties but also the binding to biological targets and thus the overall biological behavior of these compounds. Knowledge of interactions between molecules and their environment is undoubtedly the driving force of all contemporary biomedical, biological, and ecological sciences, and this knowledge is crucial for the further development and applications of these compounds.

This Special Issue is intended for all scientists involved in the synthesis/isolation, structural aspects, and analysis of heterocycles; the design, discovery, and development of biologically active heterocyclic compounds; and materials and their interactions, including their eco(toxico)logical effects. Both theoretical papers and manuscripts dealing with the mentioned topics experimentally are welcome, as are contributions dealing with the structure of receptors or enzymatic cascades.

Prof. Dr. Josef Jampilek
Guest Editor

Manuscript Submission Information

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Keywords

  • heterocycles
  • bioactive molecules and materials
  • pharmacophore
  • design
  • targeting
  • computer studies
  • synthesis and analysis
  • natural compounds
  • carbohydrates
  • physicochemical properties
  • biological screening

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Published Papers (5 papers)

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Research

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34 pages, 2064 KB  
Article
Stereoselective Synthesis of Axially Chiral 5,5′-Linked bis-1-Arylisochromans with Antibacterial Activity
by Zoltán Czenke, Attila Mándi, Gergely Miklós Fedics, Roland Albert Barta, Attila Kiss-Szikszai, Anna Kurucz-Szabados, István Timári, Attila Bényei, Sándor Balázs Király, Eszter Ostorházi, Changsheng Zhang, Máté Kicsák and Tibor Kurtán
Int. J. Mol. Sci. 2025, 26(16), 7777; https://doi.org/10.3390/ijms26167777 - 12 Aug 2025
Viewed by 281
Abstract
Inspired by naturally occurring bis-isochromans such as penicisteckins, we envisaged the first synthesis of biaryl-type bis-1-arylisochromans containing a stereogenic ortho-trisubstituted biaryl axis. We achieved the stereoselective synthesis of 5,5′-linked heterodimeric bis-isochromans containing both central and axial chirality elements by [...] Read more.
Inspired by naturally occurring bis-isochromans such as penicisteckins, we envisaged the first synthesis of biaryl-type bis-1-arylisochromans containing a stereogenic ortho-trisubstituted biaryl axis. We achieved the stereoselective synthesis of 5,5′-linked heterodimeric bis-isochromans containing both central and axial chirality elements by performing diastereoselective Suzuki–Miyaura biaryl coupling reactions on two optically active 1-arylpropan-2-ol derivatives, followed by two oxa-Pictet–Spengler cyclizations with aryl aldehydes or methoxymethyl chloride. We studied the diastereoselectivity of the cyclization step, separated the stereoisomeric products with chiral preparative HPLC and determined the absolute configuration through a combination of vibrational circular dichroism (VCD), NMR and single-crystal X-ray diffraction analysis. We demonstrated that different aryl groups could be introduced into the two isochroman subunits, since the dimethoxyaryl subunit reacted faster, enabling the two oxa-Pictet–Spengler cyclizations to be performed separately with different aryl aldehydes. We also explored the acid-catalyzed isomerization and oxidation to axially chiral ortho-quinones in order to produce stereoisomeric and oxidized analogs, respectively. We identified the antibacterial activity of our target bis-isochromans against Bacillus subtilis and Enterococcus faecalis with minimum inhibitory concentrations down to 4.0 and 0.5 μg/mL, respectively, which depend on the stereochemistry and substitution pattern of the bis-isochroman skeleton. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis, Design, and Biological Activity)
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23 pages, 8658 KB  
Article
Efficient Synthesis of Core-Fluorinated BODIPY-3,5-Diamides
by Victoria E. Shambalova, Sofiya R. Mikheeva, Alexander S. Aldoshin, Anna A. Moiseeva, Evgeniya A. Safonova, Yulia G. Gorbunova and Valentine G. Nenajdenko
Int. J. Mol. Sci. 2025, 26(10), 4484; https://doi.org/10.3390/ijms26104484 - 8 May 2025
Viewed by 657
Abstract
A modular synthesis of a new family of core-fluorinated BODIPYs was elaborated. β-Fluoro-β-nitrostyrenes were used as starting materials to prepare a set of mono-fluorinated pyrrole-2-amides using the Barton-Zard reaction with 2-isocyanoacetamides. The prepared monofluorinated building blocks were successively transformed into [...] Read more.
A modular synthesis of a new family of core-fluorinated BODIPYs was elaborated. β-Fluoro-β-nitrostyrenes were used as starting materials to prepare a set of mono-fluorinated pyrrole-2-amides using the Barton-Zard reaction with 2-isocyanoacetamides. The prepared monofluorinated building blocks were successively transformed into the corresponding dipyrromethanes and 1,7-difluoro-BODIPY-3,5-diamides. As a result, a new family of luminophores with a combination of fluorescence and photosensitizing properties was obtained. The photophysical properties of novel BODIPYs were studied by UV-vis and fluorescence spectroscopy, cyclic voltammetry and DFT calculations. In addition, their ability to generate singlet oxygen was assessed. The properties of 1,7-difluoro-BODIPY-3,5-diamides were compared with their analogues to reveal the substituent effect at the 3,5-positions. The fluorescent properties of the obtained dyes were significantly improved in comparison to their 3,5-diester analogous. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis, Design, and Biological Activity)
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21 pages, 4294 KB  
Article
Novel 5-Oxopyrrolidine-3-carbohydrazides as Potent Protein Kinase Inhibitors: Synthesis, Anticancer Evaluation, and Molecular Modeling
by Ingrida Tumosienė, Maryna Stasevych, Viktor Zvarych, Ilona Jonuškienė, Kristina Kantminienė and Vilma Petrikaitė
Int. J. Mol. Sci. 2025, 26(7), 3162; https://doi.org/10.3390/ijms26073162 - 29 Mar 2025
Viewed by 991
Abstract
A series of novel hydrazones bearing diphenylamine and 5-oxopyrrolidine moieties, along with benzene and naphthalene rings substituted with hydroxy, alkoxy, or carboxylic groups, were synthesized. Their anticancer activity was evaluated in vitro using both 2D (MTT and ‘wound healing’ assays) and 3D (cell [...] Read more.
A series of novel hydrazones bearing diphenylamine and 5-oxopyrrolidine moieties, along with benzene and naphthalene rings substituted with hydroxy, alkoxy, or carboxylic groups, were synthesized. Their anticancer activity was evaluated in vitro using both 2D (MTT and ‘wound healing’ assays) and 3D (cell spheroid) models against human melanoma IGR39 cells, the triple-negative breast cancer cell line MDA-MB-231, and pancreatic carcinoma Panc-1 cell line. Compounds 8 (2-hydroxybenzylidene derivative) and 12 (2-hydroxynaphthalenylmethylene derivative) demonstrated the highest cytotoxicity in both 2D and 3D assays, while compounds 4 (2,5-dimethoxybenzylidene derivative) and 6 (2,4,6-trimethoxybenzylidene derivative) were most effective at inhibiting cell migration. Notably, all compounds exhibited lower activity against the Panc-1 cancer cell line in a cell monolayer, but the effects on spheroid cell viability in 3D models were comparable across all tested cancer cell lines. Molecular docking studies of the most active hydrazones suggested that these compounds may act as multikinase inhibitors. In particular, 2-hydroxynaphthalenylmethylene derivative 12 showed high binding affinity values (−11.174 and −11.471 kcal/mol) to the active sites of two key protein kinases—a non-receptor TK (SCR) and STPK (BRAF)—simultaneously. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis, Design, and Biological Activity)
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Review

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28 pages, 3350 KB  
Review
Pyrazolo[5,1-c][1,2,4]triazole: A Promising Emerging Biologically Active Scaffold in Medicinal Chemistry
by Beniamin-Nicolae Pintea, Vasilica-Georgiana Panțîr, Valentin Badea and Francisc Péter
Int. J. Mol. Sci. 2025, 26(17), 8190; https://doi.org/10.3390/ijms26178190 - 23 Aug 2025
Viewed by 57
Abstract
Nitrogen-containing heterocycles are essential compounds in nature, and their structural and functional diversity inspired the synthesis of a wide range of derivatives with diverse applications as pharmaceuticals, agrochemicals, dyes, polymers, cosmetics, etc. Among them, N-fused heterocycles represent an important category, due to [...] Read more.
Nitrogen-containing heterocycles are essential compounds in nature, and their structural and functional diversity inspired the synthesis of a wide range of derivatives with diverse applications as pharmaceuticals, agrochemicals, dyes, polymers, cosmetics, etc. Among them, N-fused heterocycles represent an important category, due to their high potential as biologically active agents. Pyrazolo[5,1-c][1,2,4]triazoles, a class of nitrogen heterobicycles, have multiple applications as dyes and pigments. Also, a number of compounds containing this structure have been investigated for their biological activities. All the main experimental results published in the literature (both articles and patents) regarding the latter are summarized in this review. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis, Design, and Biological Activity)
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36 pages, 13579 KB  
Review
Therapeutic Potential of Tricyclic Pyridazinone-Based Molecules: An Overview
by Battistina Asproni, Gérard A. Pinna, Paola Corona, Silvia Coinu, Sandra Piras, Antonio Carta and Gabriele Murineddu
Int. J. Mol. Sci. 2025, 26(8), 3806; https://doi.org/10.3390/ijms26083806 - 17 Apr 2025
Viewed by 1122
Abstract
Pyridazin-3(2H)one-based molecules have always attracted the attention of medicinal chemists due to their different pharmacological properties. The incorporation of such nuclei in therapeutically active molecules either as monocyclic units or as fused bi- or tricyclic scaffolds results in a wide range [...] Read more.
Pyridazin-3(2H)one-based molecules have always attracted the attention of medicinal chemists due to their different pharmacological properties. The incorporation of such nuclei in therapeutically active molecules either as monocyclic units or as fused bi- or tricyclic scaffolds results in a wide range of pharmacological effects such as anti-inflammatory, analgesic, anticancer, antimicrobial, antiviral, cardiovascular-protective, antiulcer, and many other useful pharmacological activities. In accordance with our consolidated experience gained over the years in the chemistry and biology of tricyclic pyridazin-3(2H)ones, this review summarizes SAR studies of such pyridazinone-based polycyclic compounds endowed with various biological and therapeutic properties. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis, Design, and Biological Activity)
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