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Pharmaceuticals
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Heterocyclic Compounds in Medicinal Chemistry, 2nd Edition
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Heterocyclic Compounds in Medicinal Chemistry, 2nd Edition

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

Deadline for manuscript submissions: 20 February 2026 | Viewed by 8863

Special Issue Editors

Dr. Valentina Noemi Madia

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Guest Editor
Department of Science, Section of Biomedical Sciences and Technologies, Roma Tre University, Viale Guglielmo Marconi 446, 00146 Rome, Italy
Interests: drug design and synthesis; medicinal chemistry; organic synthesis; antimicrobial agents; structure–activity relationship; antiviral agents; antiparasitic agents; anticancer agents; antiprotozoal agents
Special Issues, Collections and Topics in MDPI journals
Dr. Davide Ialongo

E-Mail Website
Guest Editor
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy
Interests: synthesis of heterocycles; medicinal chemistry; organic chemistry; medicinal chemistry and drug design; medicinal chemistry CNS drug discovery and delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Most of the organic compounds used as therapeutics, as well as intermediates utilized for their synthesis, contain heterocyclic motifs. A heterocycle is a ring with at least one atom that is not carbon. Nitrogen, oxygen, and sulfur are the primary elements seen in common heterocycles, and they play a critical role in drug discovery. Furthermore, there are a plethora of natural products which are heterocycles that serve as the basis for many different substances, including alkaloids, vitamins, hormones, dyes, antibiotics, herbicides, or nutraceuticals. Over the past decades, much attention has been devoted to the development and pharmacological studies of heteroaromatic organic compounds that are currently considered privileged scaffolds for different therapeutic agents. Indeed, they are involved in a wide range of biological activities, representing nearly 60% of all FDA-approved drugs. This Special Issue will publish research papers with topics including, but not limited to, the preparation of aromatic and non-aromatic heterocycles endowed with any biological action. We also welcome contributions that highlight the importance of heterocyclic scaffolds that are widely found in agrochemicals, dyes, cosmetics, and functional materials. The aim of the present Special Issue is primarily to present an overview of the state-of-the-art synthetic methods and recent advances in the synthesis of heterocycles.

This Special Issue is dedicated to the memory of our dearest colleague and friend, Dr. Luca Pescatori, whose entire life, unjustly interrupted prematurely, was devoted not only to the scientific career in the field of medicinal chemistry, but certainly also at cheering up the existence of all those who had the honor of being by his side.

Dr. Valentina Noemi Madia
Dr. Davide Ialongo
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

  • heterocycles
  • drug design
  • drug discovery
  • bioactive compounds
  • structure-based drug design
  • structure–activity relationship
  • in silico studies
  • ADMET properties
  • multicomponent reactions
  • phytochemicals

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Published Papers (5 papers)

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Research

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16 pages, 3734 KB  
Article
Elucidation of a Novel Dual Binding Site on Tubulin: Theoretical Insights and Prospective Hybrid Inhibitors
by Dmytro Khylyuk, Oleg M. Demchuk, Rafał Kurczab, Barbara Miroslaw and Monika Wujec
Pharmaceuticals 2026, 19(1), 3; https://doi.org/10.3390/ph19010003 - 19 Dec 2025
Viewed by 280
Abstract
Background/Objectives: Microtubule-targeting agents remain foundational components of anticancer chemotherapy, yet their clinical utility is constrained by resistance and toxicity. Methods: Here, we present a theoretical exploration of a plausible “dual” binding pocket that spans the α-tubulin pironetin site and the inter-subunit todalam site. [...] Read more.
Background/Objectives: Microtubule-targeting agents remain foundational components of anticancer chemotherapy, yet their clinical utility is constrained by resistance and toxicity. Methods: Here, we present a theoretical exploration of a plausible “dual” binding pocket that spans the α-tubulin pironetin site and the inter-subunit todalam site. Eight virtual chimeric ligands, each merging key pharmacophoric elements of pironetin and todalam, were constructed and covalently docked to Cys316 of α-tubulin. Results: Covalent docking followed by 200 ns all-atom molecular dynamics simulations revealed that two derivatives (compounds 4 and 8) stably occupy the merged cavity, simultaneously anchoring in the pironetin region via Michael addition and in the todalam region via π-stacking and hydrogen bonding. These hybrids preserved the critical hydrogen-bonding networks of both parent ligands and exhibited low ligand RMSD values (~1.5 Å) and compact radii of gyration throughout the simulations, indicating a tight, persistent binding. Estimated HYDE affinities of 1.5 µM for compound 4 and 17.6 µM for compound 8, calculated with SeeSAR, suggest that covalent engagement can compensate for moderate non-covalent binding scores. Conclusions: In summary, our results provide compelling grounds for developing a new class of α-tubulin inhibitors that engage the hybrid pocket, laying a foundation for the structure-guided synthesis of first-in-class dual-site compounds capable of overcoming resistance to conventional microtubule-targeting drugs. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry, 2nd Edition)
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15 pages, 10674 KB  
Article
Structure-Based Virtual Screening for KHK-A Inhibitors with Anti-Hepatocellular Carcinoma Activity
by Jiang-Yi Zhu, Xiao-Yang Han, Zi-Ying Zhou, Yue-Yue Guo, Hao-Tian Duan, Jia-Jia Shen and Si-Tu Xue
Pharmaceuticals 2025, 18(12), 1865; https://doi.org/10.3390/ph18121865 - 6 Dec 2025
Viewed by 358
Abstract
Background: Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and is associated with a poor prognosis. Oxidative stress is a key factor in the occurrence and progression of HCC. KHK-A, a key protein in the oxidative stress pathway, plays an [...] Read more.
Background: Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and is associated with a poor prognosis. Oxidative stress is a key factor in the occurrence and progression of HCC. KHK-A, a key protein in the oxidative stress pathway, plays an important role in various cancers. This study aimed to discover small-molecule inhibitors targeting KHK-A through structure-based virtual screening, evaluate their therapeutic effects on HCC, and explore the potential of KHK-A as a therapeutic target for HCC. Methods: Based on the crystal structure of KHK-A, potential small-molecule inhibitors (HK1 to HK-24) were screened from the SPECS database using the Discovery Studio (DS) 2019 software. The effects of these compounds were evaluated through molecular docking and cellular experiments. Results: The screened compound HK-4 significantly inhibited HCC cell proliferation, migration, and invasion ex vivo. The half-maximal inhibitory concentrations (IC50) of HK-4 in HepG2, PLC/PRF/5, and HuH7 cells were 22.54 µM, 23.91 µM, and 23.38 µM, respectively. HK-4 induced G1 phase arrest and apoptosis, and reduced the protein levels of p-AKT and p-mTOR in the PI3K-AKT signaling pathway. Conclusions: Through structure-based virtual screening, this study identified HK-4, a small-molecule inhibitor of KHK-A with anti-HCC activity. Its mechanism of action is closely related to the regulation of the PI3K-AKT signaling pathway. This finding provides experimental evidence supporting KHK-A as a therapeutic target for HCC and offers a new direction for the development of novel anti-HCC drugs. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry, 2nd Edition)
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Figure 1

32 pages, 2128 KB  
Article
New Nitrogen-, Oxygen-, and Sulfur-Containing Heterocyclic Compounds as Anti-Colon Cancer Agents: Synthesis, Multitargeted Evaluations, Molecular Docking Simulations and ADMET Predictions
by Nahed Nasser Eid El-Sayed, Najeh Krayem, Hamed Ahmed Derbala, Shimaa Kamal, Syde Nasir Abbas Bukhari, Mohamed K. El-Ashrey, Zainab M. Almarhoon, Seham Soliman Alterary and Abir Ben Bacha
Pharmaceuticals 2025, 18(6), 801; https://doi.org/10.3390/ph18060801 - 27 May 2025
Cited by 1 | Viewed by 2481
Abstract
Background/Objectives: Oxidative stress, the Warburg effect, and resistance to apoptosis are key hallmarks driving colorectal tumorigenesis. This study aimed to develop novel multi-target compounds capable of modulating these pathways. Methods: A library of 24 newly synthesized compounds—incorporating annulated thiophene, thiazole, quinazolinone, 2-oxoindoline, and [...] Read more.
Background/Objectives: Oxidative stress, the Warburg effect, and resistance to apoptosis are key hallmarks driving colorectal tumorigenesis. This study aimed to develop novel multi-target compounds capable of modulating these pathways. Methods: A library of 24 newly synthesized compounds—incorporating annulated thiophene, thiazole, quinazolinone, 2-oxoindoline, and 1,2,3-oxadiazole scaffolds, as well as N-(1-(4-hydroxy-3-methoxyphenyl)-3-oxo-3-(2-(phenylcarbamothioyl)hydrazineyl) prop-1-en-2-yl)benzamide—was evaluated for antioxidant activity (DPPH assay), PDK-1 and LDHA inhibition, cytotoxic effects against LoVo and HCT-116 colon carcinoma cells, with parallel assessment of safety profiles on normal HUVECs. The underlying anticancer mechanism of the most active compound was investigated through analysis of cell cycle distribution, apoptosis induction, intracellular reactive oxygen species levels, mitochondrial membrane potential disruption, and expression levels of apoptosis-related genes. Molecular docking assessed binding interactions within LDHA and PDK-1 active sites. The physicochemical, drug-likeness, and ADMET properties of the multi-bioactive candidates were predicted in silico. Results: Among the synthesized compounds, thiophenes 3b and 3d exhibited potent PDK-1/LDHA and DPPH/LDHA inhibitions, along with significant cytotoxic effects on LoVo/HCT-116 cells (IC50 in µM: 190.30/170.21 and 156.60/160.96, respectively), while showing minimal cytotoxicity toward HUVECs. Molecular docking revealed favorable interactions with key amino acid residues within the LDHA and/or PDK-1 active sites. Compound 3d notably induced G2/M (LoVo) and G1 (HCT-116) arrest and promoted apoptosis via enhancing ROS generation, modulating Bax/Bcl-2 expressions, disrupting mitochondrial membrane potential, and ultimately activating caspses-3. In silico predictions indicated their promising drug-likeness and pharmacokinetics, though high lipophilicity, poor solubility (especially for 3b), and potential toxicity risks were identified as limitations. Conclusions: Thiophenes 3b and 3d emerged as promising multi-target candidates; however, structural optimization is warranted to enhance their solubility, bioavailability, and safety to support further development as lead anti-colon cancer agents. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry, 2nd Edition)
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Review

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26 pages, 6886 KB  
Review
Nitropyridines in the Synthesis of Bioactive Molecules
by Alexey Starosotnikov and Maxim Bastrakov
Pharmaceuticals 2025, 18(5), 692; https://doi.org/10.3390/ph18050692 - 7 May 2025
Cited by 1 | Viewed by 4399
Abstract
Pyridines are one of the most important and promising classes of N-heterocycles actively studied in modern organic and medicinal chemistry; in particular, pyridine is a privileged structural motif in drug design. From a synthetic organic chemistry perspective, nitropyridines can be considered as convenient [...] Read more.
Pyridines are one of the most important and promising classes of N-heterocycles actively studied in modern organic and medicinal chemistry; in particular, pyridine is a privileged structural motif in drug design. From a synthetic organic chemistry perspective, nitropyridines can be considered as convenient and readily available precursors for a wide range of mono- and polynuclear heterocyclic systems demonstrating diverse activities, such as antitumor, antiviral, anti-neurodegenerative, etc. This review is an analysis of the literature on the use of nitropyridines for the synthesis of biologically active compounds, covering the period from 2015 to the present. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry, 2nd Edition)
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Scheme 1

Other

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36 pages, 15093 KB  
Systematic Review
Benzotriazole in Cancer: A Systematic Review on Preclinical Evidence and Structure–Activity Relationship
by Gabriel Mardale, Alexandra Prodea, Andreea Munteanu, Mihaela Jorgovan, Sabina Mardale, Victor Cristian Dumitrascu and Codruța Șoica
Pharmaceuticals 2026, 19(1), 77; https://doi.org/10.3390/ph19010077 - 30 Dec 2025
Viewed by 334
Abstract
Background: A benzotriazole is a heterocycle frequently used in medicinal chemistry to obtain potent drug candidates, including anticancer agents. Nonetheless, the available literature lacks a comprehensive review of the in vitro and in vivo studies regarding these derivatives. Thus, our study aims to [...] Read more.
Background: A benzotriazole is a heterocycle frequently used in medicinal chemistry to obtain potent drug candidates, including anticancer agents. Nonetheless, the available literature lacks a comprehensive review of the in vitro and in vivo studies regarding these derivatives. Thus, our study aims to review the preclinical evidence on benzotriazole derivatives that showed potential as anticancer candidates, focusing on the cytotoxicity, mechanisms of action, structure–activity relationship, and methodological rigor of the included studies. Methods: We searched PubMed, Scopus, and Web of Science and included 41 studies in our analysis following the selection process. Additionally, we assessed the risk of bias using the QUIN tool for in vitro and the SYRCLE tool for in vivo studies in order to assess the methodological rigor of the included studies. Results: The benzotriazole derivatives were classified according to their structure in four classes, namely N-derivatives, C-derivatives, fused derivatives, and organometallic compounds. The in vitro results showed that certain derivatives, such as halogen, alkyl-aryl, or natural-base hybrids, can have superior cytotoxicity compared to parent molecules, exerted through multiple mechanisms, such as apoptosis and cell cycle arrest. Additionally, the in vivo analysis highlighted that benzotriazole derivatives can reduce tumor mass in a dose-dependent manner, with only a slight degree of hepatotoxicity reported in one case. However, histopathological data were generally absent or limited and based on a very limited number of in vivo studies. Conclusions: Overall, benzotriazole derivatives remain promising candidates for cancer treatment. However, limited mechanistic and toxicity data, as well as the moderate risk of bias identified across studies, may limit our assessment. Therefore, future studies should employ more rigorous methodologies and explore the underlying anticancer and toxicity mechanisms to fully assess the therapeutic potential of benzotriazole derivatives. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry, 2nd Edition)
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