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Updated: May 8, 2026
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Recent advances in the development of acridine-based hybrids with antiproliferative activity
Mahdi Gallala1,2, Najeh Tka3, Sonia Aroui1
1Laboratory of Biochemistry, Molecular Mechanisms and Diseases Research Unit, UR12ES08, Faculty of Medicine, University of Monastir BP5019 5000 Monastir Tunisia gallalavet@gmail.com.
Abstract:
Cancer remains a leading cause of mortality worldwide, with the limitations of conventional single-target therapies, such as severe side effects and drug resistance, driving the need for innovative treatment strategies. Molecular hybridization has emerged as a powerful rational drug design approach to develop multi-target agents capable of simultaneously modulating various oncogenic pathways. Among the diverse scaffolds explored, the acridine core, a tricyclic, planar heteroaromatic structure, stands out due to its inherent DNA-intercalating ability and potent antiproliferative activity through mechanisms like topoisomerase inhibition. This review provides a comprehensive overview of recent advances (2019-2025) in the design, synthesis, evaluation, and perspectives of acridine-based hybrids as antiproliferative agents. It systematically surveys a vast array of hybrids, classifying them by their dominant secondary pharmacophores to offer a structured and practical overview of the field. Particular attention is given to structure-activity relationships (SARs), illustrating how strategic modifications can affect cytotoxicity, selectivity, and underlying mechanistic pathways. The biological evaluation of these hybrids encompasses a range of in vitro assays, including cytotoxicity against diverse human cancer cell lines, enzyme inhibition studies, antiangiogenic assays, and preliminary in vivo experiments, reflecting their multifaceted pharmacological profiles. Computational approaches, such as molecular docking, molecular dynamics, and quantitative SAR (QSAR), have further contributed mechanistic insights and informed rational optimization of pharmacokinetic and pharmacodynamic properties. The review concludes by addressing current challenges and future directions, emphasizing the transformative potential of integrating artificial intelligence (AI) with computer-aided drug design (CADD) and advanced delivery systems. By compiling these developments, this work aims to serve as a useful reference to assist researchers in the design of new, more effective acridine-based anticancer agents.
Insights
Acridine hybrids offer a promising strategy against cancer by targeting multiple pathways, overcoming limitations of traditional therapies. Research highlights their design, synthesis, and evaluation for more effective anticancer drug development.
Area of Science:
- Medicinal Chemistry
- Drug Design
- Oncology
Background:
- Cancer remains a major global health challenge, necessitating novel therapeutic strategies beyond single-target treatments due to resistance and side effects.
- Molecular hybridization enables the development of multi-target agents to simultaneously address complex oncogenic pathways.
- The acridine scaffold is a promising core structure for anticancer agents due to its DNA intercalation and topoisomerase inhibition capabilities.
Purpose of the Study:
- To provide a comprehensive review of acridine-based hybrids as antiproliferative agents, focusing on recent advances from 2019-2025.
- To systematically survey and classify these hybrids based on their secondary pharmacophores.
- To highlight structure-activity relationships (SARs) and mechanistic insights for rational drug design.
Main Methods:
- Literature review of acridine-based hybrid anticancer agents published between 2019 and 2025.
- Classification of hybrids by secondary pharmacophores.
- Analysis of structure-activity relationships (SARs) and biological evaluation data (in vitro cytotoxicity, enzyme inhibition, antiangiogenesis, in vivo studies).
- Inclusion of computational approaches (molecular docking, molecular dynamics, QSAR) for mechanistic insights.
Main Results:
- Acridine hybrids demonstrate potent antiproliferative activity through diverse mechanisms, including DNA intercalation and topoisomerase inhibition.
- Strategic modifications of the acridine core and secondary pharmacophores significantly influence cytotoxicity and selectivity.
- In vitro and preliminary in vivo studies confirm the multifaceted pharmacological profiles of these hybrids.
Conclusions:
- Acridine-based hybrids represent a significant advancement in anticancer drug design, offering multi-target therapeutic potential.
- Integration of AI, CADD, and advanced delivery systems holds promise for optimizing future acridine-based anticancer agents.
- This review serves as a valuable resource for researchers developing novel and more effective acridine-derived cancer therapies.
