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Pharmaceuticals
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Advances in Hydrazone Compounds with Anticancer Activity
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Advances in Hydrazone Compounds with Anticancer Activity

A Special Issue of Pharmaceuticals (ISSN 1424-8247) belonging to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 July 2026) | Viewed by 5697

Editors

Dr. Boryana Nikolova-Mladenova

E-Mail Website
Guest Editor
Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria
Interests: hydrazones; anticancer activity; metal complexes; lipophilicity; structure–activity relations
Prof. Dr. Mariyana Atanasova

E-Mail Website
Guest Editor
Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria
Interests: drug design; molecular docking; molecular dynamics; hydrazones; anticancer activity; structure–activity relations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hydrazones, characterized by their R-C=N-NH-R' linkage, are attracting widespread attention in medicinal chemistry as a promising class of anticancer agents. Their structural simplicity, synthetic accessibility, and diverse pharmacological activities have prompted extensive research into their anticancer potential. One important trend in this domain is the development of novel hydrazone derivatives with enhanced potency and selectivity, with structural modifications—such as the incorporation of heterocyclic rings, introduction of halogen atoms, and optimization of substituent groups, including methoxy, methyl, and amino groups—serving as strategies. Another means by which to increase activity is to include hydrazones as ligands in various metal complexes. A key area of research is therefore understanding their mechanisms of action. The conjugation of hydrazones with nanoparticles is also being examined to ensure the precise targeting of the tumor while minimizing systemic toxicity and maximizing therapeutic concentration at target sites.

This Special Issue focuses on advances in the design, synthesis, and anticancer activity of novel hydrazones and their metal complexes. Authors are encouraged to contribute original research articles, reviews, and short communications examining hydrazones that selectively target specific cancer hallmarks, leading to improved efficacy and reduced off-target effects.

Dr. Boryana Nikolova-Mladenova
Prof. Dr. Mariyana Atanasova
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-anonymized 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

  • hydrazones
  • lipophilicity
  • logP
  • anticancer activity
  • selectivity

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Published Papers (4 papers)

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Research

27 pages, 2463 KB  
Article
Design, Synthesis, and Integrated In Silico and In Vitro Evaluation of Chloro-Substituted Salicylaldehyde Benzoylhydrazones as Anticancer Agents
by Boryana Nikolova-Mladenova, Rositsa Mihaylova, Stilyana Kostova, Boris Vasilev, Irini Doytchinova and Mariyana Atanasova
Pharmaceuticals 2026, 19(9), 1387; https://doi.org/10.3390/ph19091387 - 1 Sep 2026
Abstract
Background: Building on earlier work with methoxy-, dimethoxy-, bromo-, and nitro-substituted salicylaldehyde benzoylhydrazones, we synthesized and evaluated new 4-chloro- and 5-chloro derivatives bearing an additional chlorine substituent on the hydrazide-derived phenyl ring to further explore the impact of halogenation on cytotoxic activity. [...] Read more.
Background: Building on earlier work with methoxy-, dimethoxy-, bromo-, and nitro-substituted salicylaldehyde benzoylhydrazones, we synthesized and evaluated new 4-chloro- and 5-chloro derivatives bearing an additional chlorine substituent on the hydrazide-derived phenyl ring to further explore the impact of halogenation on cytotoxic activity. Methods: Chloro-hydrazones were obtained through a one-step condensation of 4- or 5-chlorosalicylaldehyde with benzhydrazide or 2-, 3-, and 4-chlorobenzhydrazides. Their physicochemical, pharmacokinetic, ADME, lead-likeness, and drug-likeness profiles were evaluated in silico using SwissADME, ACD/Labs v9.10, and MDL QSAR v2.2.0.0.446. The synthesized compounds were structurally characterized by IR, 1H NMR, 13C NMR, and HR ESI–MS, and their cytotoxic activity was subsequently assessed by the MTT assay in selected cancer cell lines. Molecular docking was performed against ABL1 tyrosine kinase (ABL1 TK), a potential molecular target relevant to two of the investigated leukemia cell lines, using GOLD v.5.2.2 (CCDC Ltd., Cambridge, UK). Results: The chloro-substituted salicylaldehyde benzoylhydrazones exhibited pronounced, cell-type-dependent cytotoxicity, with leukemia cells being substantially more sensitive than breast carcinoma cells. Most derivatives showed low- to sub-micromolar IC50 values against SKW-3 human T-cell prolymphocytic leukemia, K-562 human chronic myeloid (myelogenous) leukemia, and BV-173 human BCR::ABL1-positive leukemia cells, with K3 and K4 exhibiting the highest activity in SKW-3 cells (IC50 = 0.5 ± 0.1 µM). K5 showed particularly strong activity against K-562 and BV-173 cells (IC50 = 0.7 ± 0.1 and 0.9 ± 0.1 µM, respectively), compared with 26.9 ± 2.4 and 21.5 ± 3.3 µM for imatinib. HL-60 human acute promyelocytic leukemia cells showed intermediate sensitivity (IC50 = 1.3–13.9 µM), whereas the activity against MCF-7 estrogen receptor-positive and MDA-MB-231 triple-negative breast carcinoma cells was more variable (1.5–32.1 and 4.1–62.5 µM, respectively). The derivatives showed high selectivity toward malignant cells relative to non-malignant CCL-1 non-malignant mouse fibroblasts, with lower-bound SI values frequently exceeding 50 and reaching >200 in SKW-3 cells. Conclusions: The chloro-substituted salicylaldehyde benzoylhydrazones exhibited pronounced and selective cytotoxicity, particularly toward leukemia cell lines, identifying this scaffold as a promising starting point for further anticancer drug-discovery studies. Full article
(This article belongs to the Special Issue Advances in Hydrazone Compounds with Anticancer Activity)
25 pages, 6789 KB  
Article
Evaluation of Pyrazolone-Based Hydrazones as Potential Therapeutic Agents Against Glioblastoma
by Giorgio Cameli, Alessia Piergentili, Eleonora Spinozzi, Alessia Tombesi, Riccardo Petrelli, Loredana Cappellacci and Maria Beatrice Morelli
Pharmaceuticals 2026, 19(9), 1335; https://doi.org/10.3390/ph19091335 - 24 Aug 2026
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Abstract
Background: Glioblastoma (GBM) is the most aggressive subtype of malignant glioma. Current therapeutic options remain limited, highlighting the need for the development of novel compounds capable of improving the efficacy of standard treatments. This study aimed to evaluate the biological activity of [...] Read more.
Background: Glioblastoma (GBM) is the most aggressive subtype of malignant glioma. Current therapeutic options remain limited, highlighting the need for the development of novel compounds capable of improving the efficacy of standard treatments. This study aimed to evaluate the biological activity of a series of pyrazolone-based hydrazone compounds (TPPs) in vitro GBM cell lines. Methods: The eight TPPs were synthesized by a nucleophilic addition reaction of different substituted hydrazines with 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylethan-1-one and tested on two human GBM cell lines, T98 and U87. The cytotoxic effects were evaluated via MTT assay. The most active compound was further investigated at IC50 and IC25 concentrations to evaluate mechanisms of cellular damage, including reactive oxygen species (ROS) production and mitochondrial membrane potential (ΔΨm) changes. Additional assays included colony formation, cell cycle analysis, and evaluation of DNA damage and apoptosis markers. Results: TPP25 exhibited the highest activity with IC50 values of 11.01 μM (95% CI: 10.42 to 11.64) and 13.12 μM (95% CI: 10.23 to 16.87) on T98 and U87 lines, respectively. Treatment induced early ROS production and mitochondrial depolarization, along with a significant reduction in colony formation. Cell cycle analysis revealed accumulation in the sub-G0 phase, consistent with increased cell death, supported by propidium iodide uptake. Furthermore, the results suggest the involvement of an apoptotic-like mechanism as supported by Annexin V positivity, γ-H2AX upregulation and transient caspase-3 activation. Conclusions: TPP25 demonstrates significant in vitro cytotoxicity, likely driven by a pro-apoptotic mechanism. This profile positions it as a potential lead compound for further preclinical evaluation, supporting its future transition into in vivo GBM models. Full article
(This article belongs to the Special Issue Advances in Hydrazone Compounds with Anticancer Activity)
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31 pages, 3933 KB  
Article
Design, Synthesis, and Biological Evaluation of N-Acyl-Hydrazone-Linked Quinazolinone Derivatives with Antioxidant, Antimicrobial, and Anticancer Potential
by Maria Coandă, Constantin Drăghici, Lucia Pintilie, Erzsébet-Eleonóra Kapronczai, Cornel Chiriță, Ioana-Cristina Marinaș, Robert-Viorel Ancuceanu, Irina Zarafu, Petre Ioniță, Denisa-Ioana Crăciun, Ariana Hudiță, Bianca Gălățeanu, Carmen Limban and Diana Camelia Nuță
Pharmaceuticals 2026, 19(1), 57; https://doi.org/10.3390/ph19010057 - 26 Dec 2025
Cited by 1 | Viewed by 2085
Abstract
Objectives: Combining two pharmacophores into one molecule with multiple applications presents interest in the field of medicinal chemistry. Quinazolinones are among privileged scaffolds due to their wide biological activities, whereas hydrazones are versatile linkers with pharmacological potential. Thus, this article focused on [...] Read more.
Objectives: Combining two pharmacophores into one molecule with multiple applications presents interest in the field of medicinal chemistry. Quinazolinones are among privileged scaffolds due to their wide biological activities, whereas hydrazones are versatile linkers with pharmacological potential. Thus, this article focused on a green method for the synthesis of new N-acyl-hydrazones of 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetohydrazide and the exploration of their biological potential. Methods: The novel N-acyl-hydrazones (1a–1f) were synthesized under microwave irradiation, using various substituted salicylaldehydes and benzaldehydes. The products were characterized by FT-IR, 1H-NMR, 13C-NMR, and HRMS. Their pharmacological profile was assessed by in silico methods and docking simulations. Biological evaluation included antioxidant, antimicrobial, and cytotoxic activities, as well as preliminary toxicity on Artemia franciscana. Results: Spectroscopic data indicated syn-E and anti-E isomers. Compound 1c showed the highest antioxidant activity. Antimicrobial assays indicated narrow-spectrum activity, with compounds 1a and 1b being most effective against C. albicans and S. aureus. Biofilm inhibition assays revealed that 1a and 1c interfered with microbial adhesion, highlighting their potential in combating biofilm-associated infections. Cytotoxicity tests on HT-29 and A431 cancer cell lines showed selective anticancer effects for compounds 1a–1d, with minimal toxicity on normal Vero cells, especially for 1b and 1d. Toxicity against Artemia franciscana correlated with in vitro cytotoxicity data, revealing low lethality for all N-acyl-hydrazones. Docking studies indicate that the antibacterial activity may involve inhibition of S. aureus DNA gyrase B, whereas the cytotoxic effects could be mediated by interaction with the EGFR kinase. Conclusions: These findings may increase the chances of identifying a lead compound in this class, supporting the further development of selected N-acyl-hydrazones and their pharmacological exploration. Full article
(This article belongs to the Special Issue Advances in Hydrazone Compounds with Anticancer Activity)
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24 pages, 1620 KB  
Article
Novel Indole-Based Sulfonylhydrazones as Potential Anti-Breast Cancer Agents: Synthesis, In Vitro Evaluation, ADME, and QSAR Studies
by Violina T. Angelova, Rositsa Mihaylova, Zvetanka Zhivkova, Nikolay Vassilev, Boris Shivachev and Irini Doytchinova
Pharmaceuticals 2025, 18(8), 1231; https://doi.org/10.3390/ph18081231 - 20 Aug 2025
Cited by 3 | Viewed by 2377
Abstract
Background: Breast cancer continues to pose a significant global health challenge despite advances in early detection and targeted therapies. The development of novel chemotherapeutic agents remains crucial, particularly those with selective cytotoxicity toward specific breast cancer subtypes. Methods: A series of [...] Read more.
Background: Breast cancer continues to pose a significant global health challenge despite advances in early detection and targeted therapies. The development of novel chemotherapeutic agents remains crucial, particularly those with selective cytotoxicity toward specific breast cancer subtypes. Methods: A series of ten hybrid indolyl-methylidene phenylsulfonylhydrazones and one bis-indole derivative were designed, synthesized, and structurally characterized using NMR and high-resolution mass spectrometry (HRMS). Prior to synthesis, in silico screening was performed to assess drug likeness and ADME-related properties. Single-crystal X-ray diffraction was conducted for compound 3e. The cytotoxic potential of the synthesized compounds was evaluated using the MTT assay against MCF-7 (ER-α⁺) and MDA-MB-231 (triple-negative) breast cancer cell lines. Additionally, quantitative structure–activity relationship (QSAR) analysis was conducted to identify key structural features contributing to activity. Results: Most compounds exhibited selective cytotoxicity against MCF-7 cells. Notably, compound 3b demonstrated the highest potency with an IC50 of 4.0 μM and a selectivity index (SI) of 20.975. Compound 3f showed strong activity against MDA-MB-231 cells (IC50 = 4.7 μM). QSAR analysis revealed that the presence of a non-substituted phenyl ring and specific indolyl substituents (5-methoxy, 1-acetyl, 5-chloro) significantly contributed to enhanced cytotoxic activity and ligand efficiency. Conclusion: The synthesized phenylsulfonylhydrazone hybrids exhibit promising and selective cytotoxicity, particularly against ER-α⁺ breast cancer cells. Structural insights from QSAR analysis provide a valuable foundation for the further optimization of this scaffold as a potential source of selective anticancer agents. Full article
(This article belongs to the Special Issue Advances in Hydrazone Compounds with Anticancer Activity)
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