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Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically...
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Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds

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

Deadline for manuscript submissions: 31 July 2026 | Viewed by 8197

Special Issue Editor

Prof. Dr. Ionel Mangalagiu

E-Mail Website
Guest Editor
Chemistry Department, Alexandru Ioan Cuza University of Iasi, 700506 Iasi, Romania
Interests: heterocycles; medicinal chemistry; anticancer; antituberculosis; microwave; ultrasounds; organic synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A literature survey revealed that heterocycles are privileged core scaffolds in medicinal chemistry, playing an essential role in drug design and reported to exhibit many biological and pharmacological activities, including antimicrobial, antiviral, anthelmintic, anti-HIV, anticancer, antiallergic, diuretics, cardiotonics, antihypertensive, antiplatelet, analgesic, anxiolytic, antidepressant, hypnotic sedative, antineurodegenerative, anti-Alzheimer’s, etc.

     Despite the recent progress in obtaining new drugs with various biological activities in medicinal chemistry, there is an urgent need, in both the pharmaceutical industry and society, for new drugs with better activity, lower toxicity and enhanced properties. One of the most promising approaches used by scientists in the design of new drugs is the Multiple Targeting Drugs (MTD) approach, where a single chemical structure interacts with two or more distinct biological targets associated with a disease, resulting in new drug candidates with improved pharmacodynamic, pharmacokinetic and toxicologic properties and better patient compliance. Usually drug candidates in the Multiple Targeting Drugs approach are classified as Hybrid Drugs (HDs) or Chimeric Drugs (CDs). However, despite the advantages described above, both HDs and CDs have some drawbacks, such as decreases in target binding efficiency, side effects, toxicity, etc.

The aim of this Special Issue is to present the latest developments in biologically active compounds with a hybrid and/or chimeric heterocyclic core, with a focus on the synthesis, structure and biological activity of these compounds.

Prof. Dr. Ionel Mangalagiu
Guest Editor

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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

  • hybrid heterocyclic compounds
  • chimeric heterocyclic compounds
  • multifactorial diseases
  • multiple targeting drugs
  • biological activity: antimicrobials, antiviral, anthelmintic, anti-HIV, anticancer, antiallergic, diuretics, cardiotonic, antihypertensive, antiplatelet, analgesic, anxiolytics, antidepressant, hypnotic sedative, antineurodegenerative, anti-Alzheimer’s etc.

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Published Papers (6 papers)

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Research

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20 pages, 1163 KB  
Article
Novel 8-trifluoromethylquinobenzothiazines—Synthesis and Evaluation for Antiproliferative and Antibacterial Activity
by Daria Klimoszek, Anna Majewska, Małgorzata Jeleń, Marta Struga, Beata Morak-Młodawska and Małgorzata Dołowy
Pharmaceuticals 2026, 19(3), 422; https://doi.org/10.3390/ph19030422 - 4 Mar 2026
Viewed by 751
Abstract
Background: Phenothiazine derivatives bearing trifluoromethyl substituents have attracted increasing interest as multifunctional scaffolds in drug repositioning strategies, particularly in cancer and infectious diseases. Structural modification of classical phenothiazines by incorporation of a quinoline moiety has previously been shown to enhance biological activity. [...] Read more.
Background: Phenothiazine derivatives bearing trifluoromethyl substituents have attracted increasing interest as multifunctional scaffolds in drug repositioning strategies, particularly in cancer and infectious diseases. Structural modification of classical phenothiazines by incorporation of a quinoline moiety has previously been shown to enhance biological activity. Objectives: The present study aimed to develop an efficient synthesis of 8-trifluoromethylquinobenzothiazines and to evaluate the anticancer and antibacterial potential of their N-substituted analogues inspired by triflupromazine, trifluoperazine, and fluphenazine. Methods: 6H-8-Trifluoromethylquinobenzothiazine was synthesized by cyclization of 2-amino-4-trifluoromethylbenzenethiol and 3-bromo-2-chloroquinoline. The resulting quinobenzothiazine, unsubstituted at the nitrogen atom, was subjected to N-alkylation reactions to afford eleven new 6-dialkylaminoalkyl derivatives. Structural elucidation was performed using NMR and HRMS techniques. Anticancer activity was evaluated by MTT assay against human breast (MDA-MB-231), pancreatic (Mia-PaCa-2), and lung (A-549) carcinoma cell lines, as well as normal HaCaT keratinocytes. Antibacterial activity was assessed by MIC/MBC determination against selected Gram-positive and Gram-negative reference strains and clinical isolates. Results: Among the synthesized compounds, derivatives 8 and 12 exhibited the most favorable anticancer profiles, showing micromolar cytotoxicity (IC50 ≈ 4–10 µM) against lung and pancreatic cancer cells combined with moderate selectivity toward cancer cells over normal keratinocytes. Compound 6 displayed lower cytotoxic potency but a notably high selectivity index due to minimal toxicity toward normal cells. In antibacterial assays, compound 3 exhibited activity against Gram-positive bacteria, including a methicillin-resistant Staphylococcus aureus isolate, with MIC values ranging from 7.8 to 15.6 µg/mL. The corresponding MBC values were equal to or twofold higher than the MICs (MBC/MIC = 1–2), fulfilling commonly accepted criteria for bactericidal activity (MBC/MIC ≤ 4). OD-based growth kinetics confirmed concentration-dependent inhibition of S. aureus growth. Conclusions: The obtained results identify 8-trifluoromethylquinobenzothiazines as a promising class of multifunctional compounds. Selected derivatives combine anticancer activity with acceptable selectivity or display potent antibacterial effects against clinically relevant Gram-positive pathogens. Full article
(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)
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39 pages, 16563 KB  
Article
Innovative Amino-Functionalization of Pyrido[2,3-d]pyrimidine Scaffolds for Broad Therapeutic Applications Supported by Computational Analyses
by Hagar S. El-Hema, Haitham E. Shehata, Mohamed A. Hawata, Eman S. Nossier, Ahmed F. El-Sayed, Najla A. Altwaijry, Asmaa Saleh, Modather F. Hussein, Amr Sabry and Adel A.-H. Abdel-Rahman
Pharmaceuticals 2025, 18(10), 1472; https://doi.org/10.3390/ph18101472 - 30 Sep 2025
Cited by 8 | Viewed by 2249
Abstract
Background: Derivatives of Pyrido[2,3-d]pyrimidine-6-carboxylate are promising multi-target scaffolds. This study focused on synthesizing 16 amino-functionalized derivatives and evaluating their dual anticancer and antibacterial activities, supported by mechanistic and computational analyses. Objectives: Design and synthesize derivatives, evaluate cytotoxicity against HeLa, HepG-2, and [...] Read more.
Background: Derivatives of Pyrido[2,3-d]pyrimidine-6-carboxylate are promising multi-target scaffolds. This study focused on synthesizing 16 amino-functionalized derivatives and evaluating their dual anticancer and antibacterial activities, supported by mechanistic and computational analyses. Objectives: Design and synthesize derivatives, evaluate cytotoxicity against HeLa, HepG-2, and MCF-7 (selectivity against WI-38), investigate EGFRWT and EGFRT790M inhibition, assess cell cycle, apoptosis, and migration effects, antibacterial efficacy against E. coli and P. aeruginosa, and perform in silico ADMET, docking, molecular dynamics, DFT, and antiviral predictions. Methods: Synthesized 16 derivatives; tested for cytotoxicity, EGFR inhibition, cell cycle, apoptosis, migration; assessed antibacterial activity; performed ADMET profiling, molecular docking, molecular dynamics, and DFT calculations. Results: Derivatives 1, 2, and 7 showed highest cytotoxicity (IC50 = 3.98–17.52 μM; WI-38 IC50 = 64.07–81.65 μM). Compound 1 potently inhibited EGFRWT (IC50 = 0.093 μM) and EGFRT790M (IC50 = 0.174 μM), induced G0/G1 arrest (74.86%) and apoptosis (26.37%), and reduced MCF-7 migration (69.63%). Moderate antibacterial activity observed (MIC = 50 μg/mL). ADMET indicated favorable pharmacokinetics, low CYP inhibition, negative mutagenicity, and oral toxicity class III. Molecular dynamics confirmed stable binding (EGFRWT RMSD 3 Å; EGFRT790M 3.5–4.6 Å) with persistent hydrogen bonds. In silico antiviral evaluation suggested strong binding to HCV NS5A (–9.36 kcal/mol), SARS-CoV-2 Mpro (–9.82 kcal/mol), and E.coli DNA gyrase (–10.25 kcal/mol). Conclusions: Compound 1 exhibits dual anticancer and antibacterial activity, supported by mechanistic and computational analyses, highlighting pyrido[2,3-d]pyrimidines as promising multi-target therapeutic scaffolds. Full article
(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)
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Review

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30 pages, 3616 KB  
Review
Recent Advances in Benzimidazole–Triazole Hybrids for Single- and Multi-Target Protein Kinase Inhibition
by Hamzeh M. Abu Al Rub and Ahmed G. Eissa
Pharmaceuticals 2026, 19(4), 623; https://doi.org/10.3390/ph19040623 - 15 Apr 2026
Viewed by 615
Abstract
Background/Objectives: Protein kinases play a crucial role in cancer initiation, progression, and therapeutic resistance by regulating signalling pathways involved in tumour growth and survival. Consequently, they represent major targets in anticancer drug discovery. Among heterocyclic scaffolds explored in kinase inhibitor design, benzimidazole has [...] Read more.
Background/Objectives: Protein kinases play a crucial role in cancer initiation, progression, and therapeutic resistance by regulating signalling pathways involved in tumour growth and survival. Consequently, they represent major targets in anticancer drug discovery. Among heterocyclic scaffolds explored in kinase inhibitor design, benzimidazole has emerged as a privileged structure due to its strong hydrogen-bonding capability and structural resemblance to purine moieties. Triazole motifs are also widely incorporated into bioactive molecules because of their metabolic stability, favourable electronic properties, and ability to establish key interactions within kinase active sites. This review aims to summarise and critically discuss benzimidazole- and triazole-based kinase inhibitors, both as individual scaffolds and as hybrid systems, with emphasis on their kinase targets and multitarget potential. Methods: The relevant literature was surveyed from major scientific databases focusing on studies describing the synthesis, biological evaluation, and molecular modelling of benzimidazole- and triazole-containing kinase inhibitors. Results: Numerous studies demonstrate that both benzimidazole and triazole scaffolds exhibit significant kinase inhibitory activity against oncogenic targets, including EGFR, cyclin-dependent kinases (CDKs), and components of the PI3K/Akt/mTOR signalling pathway. Hybrid molecules combining these pharmacophores frequently enhance binding interactions and facilitate the development of multitarget kinase inhibitors. Structure–activity relationship trends indicate that pharmacophore accessibility, substitution patterns, and linker architecture influence inhibitory potency and selectivity. Conclusions: Overall, benzimidazole- and triazole-based scaffolds represent promising platforms for developing next-generation multitarget anticancer agents and provide valuable insights for the rational design of improved kinase inhibitors. Full article
(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)
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41 pages, 5770 KB  
Review
Azole–Flavonoid Hybrids as Emerging Anticancer Agents: A Bioactivity-Focused Review
by Mihaela Lipovanu, Anca Miron, Nina Filip, Cristina Elena Horhogea and Ana Clara Aprotosoaie
Pharmaceuticals 2026, 19(2), 338; https://doi.org/10.3390/ph19020338 - 20 Feb 2026
Viewed by 1285
Abstract
Despite notable progress in drug discovery, cancer treatment remains hindered by limited therapeutic efficacy, poor target specificity, adverse effects, and the development of drug resistance. Molecular hybridization, which integrates two or more bioactive entities into a single molecule, has shown considerable potential to [...] Read more.
Despite notable progress in drug discovery, cancer treatment remains hindered by limited therapeutic efficacy, poor target specificity, adverse effects, and the development of drug resistance. Molecular hybridization, which integrates two or more bioactive entities into a single molecule, has shown considerable potential to overcome these limitations. Since both azoles and flavonoids have demonstrated anticancer potential, extensive studies have been undertaken to combine the two entities and enhance the bioactivity of the resulting hybrids. In this context, numerous azole–flavonoid hybrids have been synthesized and investigated for their anticancer potential. This review provides an overview of the azole–flavonoid hybrids that are promising candidates for novel anticancer drug development, highlighting their superior antitumor potency compared to reference drugs, multitarget activity, tumor-selective cytotoxicity, efficacy against drug-resistant tumor cells, and structure–activity relationships. The review covers 250 hybrids, primarily triazole–chalcone hybrids but also triazole–flavone, flavanone, flavonol, and isoflavone hybrids, as well as other azole–flavonoid hybrids (imidazole–, pyrazole–, isoxazole–, and thiazole–flavonoid hybrids). Full article
(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)
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26 pages, 2480 KB  
Review
Promising Norlabdane-Heterocyclic Hybrids: Synthesis, Structural Characterization and Antimicrobial Activity Evaluation
by Lidia Lungu, Alexandru Ciocarlan, Ionel I. Mangalagiu and Aculina Aricu
Pharmaceuticals 2025, 18(9), 1411; https://doi.org/10.3390/ph18091411 - 19 Sep 2025
Viewed by 1253
Abstract
The terpeno-heterocyclic molecular hybrids are a new and promising class of modern organic and medicinal chemistry, because their molecules exhibit high and selective biological activity, natural origins, and good biocompatibility, and, usually, they are less toxic. The reported norlabdane-heterocyclic hybrids were synthesized by [...] Read more.
The terpeno-heterocyclic molecular hybrids are a new and promising class of modern organic and medicinal chemistry, because their molecules exhibit high and selective biological activity, natural origins, and good biocompatibility, and, usually, they are less toxic. The reported norlabdane-heterocyclic hybrids were synthesized by classical and new, original, and environmentally friendly methods, which include coupling reactions of norlabdane derivatives (such as carboxylic acids, acyl chlorides, or bromides) with individual heterocyclic compounds, as well as heterocyclization reactions of certain norlabdane intermediates like hydrazides, thiosemicarbazones, or hydrazinecarbothioamides. The aforementioned norlabdanes were derived from (+)-sclareolide 2, which is readily obtained from (−)-sclareol 1, a labdane-type diterpenoid extracted from the waste biomass of Clary sage (Salvia sclarea L.) that remains after essential oil extraction. All synthesized compounds were tested against various fungal strains and bacterial species, with many exhibiting significant antifungal and antibacterial activity. These findings support the potential application of the synthesized compounds in the treatment of diseases caused by fungi and bacteria. Additionally, the use of plant-based waste materials as starting resources highlights the economic and ecological value of this approach. This review summarizes experimental data on the synthesis and biological activity of norlabdane: diazine, 1,2,4-triazole and carbazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3-thiazole, 1,3-benzothiazole and 1,3-benzimidazole hybrids performed by our research group covering the period from 2013 to the present. Full article
(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)
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28 pages, 2073 KB  
Review
Hybrid and Chimeric Heterocycles for the Inhibition of Carbonic Anhydrases
by Niccolò Paoletti, Simone Giovannuzzi and Claudiu T. Supuran
Pharmaceuticals 2025, 18(9), 1387; https://doi.org/10.3390/ph18091387 - 16 Sep 2025
Cited by 1 | Viewed by 1046
Abstract
The design of multitarget drugs is a growing strategy to address complex and multifactorial diseases, and heterocycles play a major role in this approach. This review aims to critically analyze the role of heterocyclic scaffolds in the development of human carbonic anhydrase inhibitors [...] Read more.
The design of multitarget drugs is a growing strategy to address complex and multifactorial diseases, and heterocycles play a major role in this approach. This review aims to critically analyze the role of heterocyclic scaffolds in the development of human carbonic anhydrase inhibitors (hCAIs), emphasizing their versatility as core chemotypes, linkers, and secondary pharmacophores. By examining advances from the last 10 years, we highlight how heterocycle-based designs contribute to modulating potency and selectivity toward hCAs, as well as to the creation of hybrid molecules with enhanced therapeutic profiles. Understanding these strategies is essential for guiding future drug discovery efforts targeting hCAs and related pathologies. Full article
(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)
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