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Pharmaceuticals
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Advances in the Synthesis and Application of Heterocyclic Compounds
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Advances in the Synthesis and Application of Heterocyclic Compounds

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

Deadline for manuscript submissions: closed (31 December 2025) | Viewed by 13251

Special Issue Editors

Dr. Monika Olesiejuk

E-Mail Website
Guest Editor
Department of Chemical Organic Technology and Petrochemistry, The Silesian University of Technology, Krzywoustego 4, PL-44100 Gliwice, Poland
Interests: heterocyclic compounds; cross-coupling reaction; organic synthesis; azo compounds
Prof. Dr. Agnieszka Kudelko

E-Mail Website
Guest Editor
Department of Chemical Organic Technology and Petrochemistry, The Silesian University of Technology, Krzywoustego 4, PL-44100 Gliwice, Poland
Interests: heterocyclic compounds; synthesis; physical chemistry

Special Issue Information

Dear Colleagues,

The world is persistently moving forward and science is constantly developing; as a result, the knowledge of new generations is becoming enriched with new information. The world of science is filled with people who passionately explore chemistry, which we can compare to the discovery of the world by children playing with Lego blocks. Scientists are competing with each other to create new methods for the synthesis of compounds with valuable properties, for modifications of existing systems to improve their assets, or for the construction of entirely new structures in the hope of finding breakthrough activities. What once seemed impossible is now within reach.It is safe to say that when a chemical compound exhibits valuable biological properties, medicine becomes the leading area of scientists’ ​​interest. In pharmacology, heterocyclic compounds undoubtedly play a crucial role. Determining useful pharmacophores allows scientists to modify the structure of existing drugs or search for alternative solutions for specific biological targets.

This Special Issue of Pharmaceuticals aims to summarize information from original articles and reviews on new synthesis methods and applications of heterocyclic compounds in medicine.

Dr. Monika Olesiejuk
Prof. Dr. Agnieszka Kudelko
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 250 words) can be sent to the Editorial Office for assessment.

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

  • organic synthesis
  • heterocyclic compounds
  • biological activity
  • medicine
  • therapeutics

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Published Papers (6 papers)

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Research

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18 pages, 639 KB  
Article
Synthesis, Characterization, Antimicrobial and Anticancer Evaluation of Novel Heterocyclic Diazene Compounds Derived from 8-Quinolinol
by Ion Burcă, Alexandra-Mihaela Diaconescu, Valentin Badea and Francisc Péter
Pharmaceuticals 2026, 19(1), 4; https://doi.org/10.3390/ph19010004 - 19 Dec 2025
Viewed by 385
Abstract
Background: 8-Quinolinol and its derivatives are drawing significant attention across various disciplines due to their remarkable versatility. These compounds are well-known for their exceptional chelating ability, forming stable metal complexes via their nitrogen and oxygen electron donor atoms. This main characteristic determines [...] Read more.
Background: 8-Quinolinol and its derivatives are drawing significant attention across various disciplines due to their remarkable versatility. These compounds are well-known for their exceptional chelating ability, forming stable metal complexes via their nitrogen and oxygen electron donor atoms. This main characteristic determines their broad utility. Biological activity can also be explained by the chelating capacity, which allows 8-quinolinol to bind to essential metal ions such as Fe, Zn, Cu, and others. This chelation disrupts metal-dependent biological processes in target cells or organisms, leading to a range of effects, including antimicrobial, anticancer, antifungal, and neuroprotective activities. On the other hand, the biological activity of pyrazole derivatives is attributed to their heterocyclic structure, which allows for interactions with biological targets that can lead to enzyme inhibition, receptor antagonism, radical scavenging, and other effects. Objective: This work aimed to synthesize and characterize novel diazene compounds derived from 8-quinolinol or 2-methyl-8-quinolinol and pyrazole amines, and to evaluate their antimicrobial and anticancer activities. Methods: The compounds have been synthesized by coupling diazonium salts obtained from the diazotization of heterocyclic amines with 8-quinolinol and its derivative, 2-methyl-8-quinolinol. The careful selection of reaction conditions enabled the synthesis of high-purity products. The compounds were characterized by 1D and 2D NMR, FT-IR spectroscopy, UV-Vis spectroscopy, and LC-HRMS analysis. The biological activity of the newly synthesized compounds was evaluated following the protocols of EU-OPENSCREEN, a European Research Infrastructure Consortium (ERIC) initiative dedicated to supporting early drug discovery. Results: By combining diazonium salts obtained from 3-methyl-1H-pyrazol-5-amine and ethyl 5-amino-3-methyl-1H-pyrazole-4-carboxylate with the aforementioned coupling agents, four novel 8-quinolinol derivatives were synthesized. The further hydrolysis of the ethoxy carbonyl functional group allowed its conversion to a carboxylic functional group, thus expanding the series of new compounds to six members. Several compounds from the series have proven to be biologically active against several human pathogenic microorganisms and the Hep-G2 cancer cell line. Conclusions: The combination of two well-known biologically active scaffolds through a classic diazo coupling reaction allowed the synthesis of novel biologically active compounds, which showed promising results as possible antifungal and anticancer agents. These results represent a foundation for future studies, which will include a broader biological screening and in vivo studies. Full article
(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)
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51 pages, 5968 KB  
Article
Structure–Activity Relationship Study of 3-Alkynyl-6-aryl-isothiazolo[4,3-b]pyridines as Dual Inhibitors of the Lipid Kinases PIKfyve and PIP4K2C
by Demian Kalebic, Ling-Jie Gao, Belén Martinez-Gualda, Marwah Karim, Sirle Saul, Do Hoang Nhu Tran, Jef Rozenski, Leentje Persoons, Dominique Schols, Wim Dehaen, Shirit Einav and Steven De Jonghe
Pharmaceuticals 2025, 18(9), 1341; https://doi.org/10.3390/ph18091341 - 6 Sep 2025
Cited by 1 | Viewed by 1584
Abstract
Background/Objectives: RMC-113, a 3-alkynyl-6-aryl-disubstituted isothiazolo[4,3-b]pyridine, is a dual inhibitor of the lipid kinases PIKfyve and PIP4K2C with broad-spectrum antiviral activity. The aim was to study the structure–activity relationship (SAR) of isothiazolo[4,3-b]pyridines as dual PIKfyve/PIP4K2C inhibitors. Methods: A [...] Read more.
Background/Objectives: RMC-113, a 3-alkynyl-6-aryl-disubstituted isothiazolo[4,3-b]pyridine, is a dual inhibitor of the lipid kinases PIKfyve and PIP4K2C with broad-spectrum antiviral activity. The aim was to study the structure–activity relationship (SAR) of isothiazolo[4,3-b]pyridines as dual PIKfyve/PIP4K2C inhibitors. Methods: A series of isothiazolo[4,3-b]pyridines was synthesized by introducing structural variety at positions 3 and 6 of the central scaffold. The primary assay to guide the synthetic chemistry was a biochemical PIKfyve assay, with a number of analogues also tested for PIP4K2C binding affinity. Finally, isothiazolo[4,3-b]pyridines were also evaluated for antiviral and antitumoral activity in cell-based assays. Results: PIKfyve inhibition tolerated a wide variety of substituents on the aryl ring at position 6 of the isothiazolo[4,3-b]pyridine scaffold, with the 4-carboxamide analogue emerging as the most potent (IC50 = 1 nM). The SAR at position 3 was more restricted, although the introduction of electron-donating groups (such as a methyl and methoxy) on the pyridinyl ring yielded potent PIKfyve inhibitors, with IC50 values in the low nM range. The acetylenic moiety was essential for PIKfyve inhibition, and only the saturated ethyl linker displayed potent PIKfyve inhibition, albeit less active than the acetylene counterpart. The compounds were 2- to 5-fold less potent on PIP4K2C relative to PIKfyve. These dual PIKfyve/PIP4K2C inhibitors displayed antiviral activity against both the venezuelan equine encephalitis virus (VEEV) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A screening against a panel of cancer cell lines revealed antitumoral activity, although some of the potent PIKfyve/PIP5K2C inhibitors lacked antitumoral activity. Conclusions: Isothiazolo[4,3-b]pyridines are dual PIKfyve/PIP4K2C inhibitors displaying broad-spectrum antiviral, as well as antitumoral, activity. Full article
(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)
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Review

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32 pages, 4721 KB  
Review
Benzimidazole-Quinoline Hybrids: Synthesis and Antimicrobial Properties
by Maria Marinescu
Pharmaceuticals 2026, 19(1), 180; https://doi.org/10.3390/ph19010180 - 20 Jan 2026
Abstract
Background: Heterocyclic compounds are particularly important in medicinal chemistry. With a range of therapeutic uses, benzimidazoles and quinolines are both key heterocycles in medicinal chemistry. A number of hybrid heterocyclic compounds have been reported in recent years because they typically have better [...] Read more.
Background: Heterocyclic compounds are particularly important in medicinal chemistry. With a range of therapeutic uses, benzimidazoles and quinolines are both key heterocycles in medicinal chemistry. A number of hybrid heterocyclic compounds have been reported in recent years because they typically have better therapeutic properties than single heterocyclic rings. Methods: A literature search was conducted across relevant scientific literature from peer-reviewed sources, using keywords, including “benzimidazole”, “quinoline”, “benzimidazole-quinoline hybrids”, “antibacterial”, “antifungal”, “antimalarial” and “hybrid complexes”. Results: This review summarizes the synthetic methodologies for benzimidazole–quinoline hybrids, benzimidazole– quinolinones, and benzimidazole–quinoline metal complexes, along with their antimicrobial and antimalarial activities and the reported structure–activity relationship (SAR) studies. The importance of halogen substitution, particularly with chlorine and fluorine atoms, as well as the structure of the linker between the benzimidazole and quinoline rings—specifically chain length, the presence of oxygen, sulfur, or nitrogen atoms, and heterocyclic moieties—is highlighted. A series of benzimidazole–quinoline hybrids exhibit antimalarial and antitrypanosomal activities or show enhanced antimicrobial properties due to the incorporation of a five-membered heterocycle in addition to the two existing heterocyclic rings. Notably, several hybrids from different compound series exhibit very low minimum inhibitory concentrations (MICs) in the range of 1–8 µg/mL, along with low cytotoxicity, supporting their potential for further investigation as antimicrobial agents. Conclusions: This review summarizes the synthetic methods, medicinal properties, and structure–activity relationship (SAR) studies of benzimidazole–quinoline hybrids reported between 2002 and 2026. Full article
(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)
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40 pages, 2388 KB  
Review
A Review on Sulfonamide Complexes with Metals: Their Pharmacological Potential as Anticancer Drugs
by Przemysław Rozbicki and Danuta Branowska
Pharmaceuticals 2025, 18(9), 1414; https://doi.org/10.3390/ph18091414 - 19 Sep 2025
Viewed by 1465
Abstract
Sulfonamides represent a versatile class of biologically active compounds, best known for their antibacterial activity, but increasingly investigated for their potential in oncology. Free sulfonamides themselves display cytotoxic properties; however, coordination with metal ions often enhances both selectivity and potency, while also introducing [...] Read more.
Sulfonamides represent a versatile class of biologically active compounds, best known for their antibacterial activity, but increasingly investigated for their potential in oncology. Free sulfonamides themselves display cytotoxic properties; however, coordination with metal ions often enhances both selectivity and potency, while also introducing new mechanisms of action. Although numerous studies have reported sulfonamide–metal complexes with anticancer activity, a systematic overview linking biological properties to the central metal atom has been lacking. This review summarizes current research on sulfonamide complexes with transition metals and selected main-group elements, focusing on their pharmacological potential as anticancer agents. The compounds discussed include complexes of titanium, chromium, manganese, rhenium, ruthenium, osmium, iridium, palladium, platinum, copper, silver, gold, iron, cobalt, nickel, uranium, calcium, magnesium and bismuth. For each group, representative structures are presented along with cytotoxicity data against cancer cell lines, comparisons with reference drugs such as for example cisplatin, and where relevant, studies on carbonic anhydrase inhibition. The survey of available data demonstrates that many sulfonamide–metal complexes show cytotoxic activity comparable to or greater than existing chemotherapeutic agents, while in some cases exhibiting reduced toxicity toward non-cancerous cells. These findings highlight the promise of sulfonamide–metal complexes as a fertile area for anticancer drug development and provide a framework for future design strategies. This review covers the research on anti-cancer activity of sulfonamide complexes during the years 2007–2025. Full article
(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)
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74 pages, 8029 KB  
Review
Antimicrobial Activity of 1,3,4-Thiadiazole Derivatives
by Sebastian Górecki, Agnieszka Kudelko and Monika Olesiejuk
Pharmaceuticals 2025, 18(9), 1348; https://doi.org/10.3390/ph18091348 - 8 Sep 2025
Cited by 2 | Viewed by 3599
Abstract
The 1,3,4-thiadiazole core has attracted significant attention due to its unique electronic structure, physicochemical properties, and wide-ranging pharmacological potential. This heterocyclic scaffold exhibits a broad spectrum of biological activities, often attributed to its capacity to modulate enzyme function, interact with receptors, and disrupt [...] Read more.
The 1,3,4-thiadiazole core has attracted significant attention due to its unique electronic structure, physicochemical properties, and wide-ranging pharmacological potential. This heterocyclic scaffold exhibits a broad spectrum of biological activities, often attributed to its capacity to modulate enzyme function, interact with receptors, and disrupt key biochemical pathways in both pathogens and host cells. Additionally, 1,3,4-thiadiazoles typically display favorable pharmacokinetic properties, including high metabolic stability and appropriate lipophilicity, which enhance their drug-likeness and bioavailability. This review presents an overview of antibacterial and antifungal compounds bearing the 1,3,4-thiadiazole scaffold that have been reported over the past five years. This publication details the chemical structures of novel 1,3,4-thiadiazole derivatives and reports the results of antibacterial and antifungal activity assays conducted against a range of microbial strains. Furthermore, it provides conclusions regarding the structural features that influence the observed biological activity of the synthesized compounds. Antimicrobial activity assessments conducted against ten Gram-negative and nine Gram-positive bacterial strains revealed that 79 newly synthesized 1,3,4-thiadiazole derivatives exhibited either superior inhibitory efficacy relative to standard reference antibiotics or achieved a high level of bacterial growth suppression, defined as 90–100% inhibition. In antifungal assays, the compounds were evaluated against 25 fungal species representing 15 genera. Among the tested derivatives, 75 compounds demonstrated antifungal potency exceeding that of reference antifungal agents or produced growth inhibition within the 90–100% range. The information provided herein may serve as a valuable resource for medicinal and agricultural chemists engaged in the development of novel drug candidates and plant protection agents. Full article
(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)
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23 pages, 8189 KB  
Review
Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery
by Taegwan Kim, Eunbee Baek and Jonghoon Kim
Pharmaceuticals 2025, 18(5), 617; https://doi.org/10.3390/ph18050617 - 24 Apr 2025
Cited by 6 | Viewed by 5649
Abstract
Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity to target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein interfaces. However, despite their potential, the synthesis [...] Read more.
Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity to target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein interfaces. However, despite their potential, the synthesis and optimization of macrocyclic compounds present considerable challenges related to structural complexity, synthetic accessibility, and the attainment of favorable drug-like properties, particularly cell permeability and oral bioavailability. Recent advancements in synthetic methodologies have expanded the chemical space accessible to macrocycles, enabling the creation of structurally diverse and pharmacologically active compounds. Concurrent developments in computational strategies have further enhanced macrocycle design, providing valuable insights into structural optimization and predicting molecular properties essential for therapeutic efficacy. Additionally, a deeper understanding of macrocycles’ conformational adaptability, especially their ability to internally shield polar functionalities to improve membrane permeability, has significantly informed their rational design. This review discusses recent innovations in synthetic and computational methodologies that have advanced macrocycle drug discovery over the past five years. It emphasizes the importance of integrating these strategies to overcome existing challenges, illustrating how their synergy expands the therapeutic potential and chemical diversity of macrocycles. Selected case studies underscore the practical impact of these integrated approaches, highlighting promising therapeutic applications across diverse biomedical targets. Full article
(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)
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