Emerging Role of Acridine Nucleus in The Treatment of Rare and Neglected Diseases: A Review

Rare and neglected diseases collectively represent a substantial yet often overlooked global health burden. Rare diseases are defined differently across regulatory regions; for example, the U.S. Food and Drug Administration define a rare disease as a condition^[39,40] affecting fewer than 200,000 individuals in the United States, whereas the European Medicines Agency considers diseases affecting fewer than 5 in 10,000 people as rare. Despite their individual rarity, over 7,000 identified rare diseases together affect millions worldwide, with limited therapeutic options available.^[32,37]

Neglected tropical diseases (NTDs),^[38] as recognized by the World Health Organization, primarily affect populations in low- and middle-income countries and include infections such as malaria, leishmaniasis, and trypanosomiasis. These diseases are strongly associated with poverty, inadequate sanitation, and restricted access to healthcare, resulting in significant morbidity and socioeconomic loss.

In modern drug discovery, heterocyclic scaffolds play a central role due to their structural diversity and biological adaptability.^[1,9,14,28] Among them, the acridine nucleus, a planar tricyclic nitrogen-containing system, has attracted sustained interest because of its DNA intercalating ability, enzyme inhibition potential, and broad pharmacological profile.^[3,27] Historically used in antimicrobial and anticancer therapy, acridine derivatives such as Quinacrine and Amsacrine demonstrate the clinical relevance of this scaffold.

Recent advances in medicinal chemistry, including structure–activity relationship optimization, hybrid pharmacophore development, and drug repurposing strategies, have renewed attention toward acridine-based compounds for rare and neglected diseases.      Therefore, this review aims to comprehensively summarize the chemical features, pharmacological mechanisms, and emerging therapeutic applications of the acridine nucleus in addressing unmet medical needs.

Fig. 1 : Global impact of rare & neglected diseases

CHEMISTRY OF ACRIDINE NUCLEUS

Historical Background

Acridine is a nitrogen-containing tricyclic heteroaromatic compound structurally related to anthracene, in which one central carbon atom is replaced by nitrogen. It was first isolated from coal tar in the late 19th century and initially explored for its dyeing properties. Early derivatives demonstrated antiseptic activity, which led to the development of clinically useful compounds such as Quinacrine.^[12,15] Over time, the acridine scaffold gained prominence in medicinal chemistry due to its ability to interact with nucleic acids and enzymes, paving the way for anticancer agents like Amsacrine.

Structural Features

The acridine nucleus consists of three fused aromatic rings forming a rigid, planar system with a nitrogen atom at the 10-position. This planar geometry facilitates intercalation between DNA base pairs, a property central to many of its biological activities.

Key chemical features include:

• Aromatic π-electron system enabling stacking interactions
• Basic nitrogen atom allowing protonation and salt formation
• Possibility of substitution at multiple positions (2, 4, 6, 9 positions commonly modified)
• Tunable lipophilicity and electronic properties

These characteristics make acridine a privileged scaffold in drug design.

Fig. 2 : Acridine Nucleus

Synthetic Approaches

Several classical and modern synthetic routes are used^[6,8] to construct the acridine core:

Bernthsen Acridine Synthesis

One of the earliest methods, involving condensation of diphenylamine with carboxylic acids in the presence of zinc chloride.^[16]

Scheme 1 : Synthesis of Acridine using Bernthsen method

Ullmann-Type and Cyclization Reactions

Copper-catalyzed coupling reactions and intramolecular cyclization strategies enable substituted acridine derivatives.^[26]

Scheme 2 : Ullmann Reaction

Modern Green and Catalytic Methods

Recent advancements include:

• Microwave-assisted synthesis
• Metal-catalyzed cross-coupling reactions
• Solvent-free and eco-friendly methodologies

Scheme 3 : Green synthesis of acridine derivates

These approaches allow structural diversification, essential for structure–activity relationship (SAR) optimization in rare and neglected disease drug discovery.

PHARMACOLOGICAL PROFILE OF ACRIDINE DERIVATIVES

DNA Intercalation Mechanism

One of the most characteristic properties of acridine derivatives is their ability to intercalate into DNA.^[7,17] The planar tricyclic structure enables insertion between adjacent base pairs, stabilizing the DNA–drug complex through π–π stacking interactions. This intercalation can interfere with DNA replication and transcription processes, ultimately leading to inhibition of cell proliferation. Certain derivatives also inhibit topoisomerase enzymes, contributing to their anticancer and antiparasitic effects. The clinical use of Amsacrine is based on such mechanisms.^[2,10,11,13]

Fig 3 : DNA Intercalation mechanism

Antimicrobial Activity

Acridine compounds exhibit broad-spectrum antimicrobial activity.

Antibacterial Activity

They disrupt bacterial DNA function and membrane integrity. Early acridine dyes were widely used as topical antiseptics.

Antifungal Activity

Some substituted acridines demonstrate fungistatic effects by interfering with nucleic acid synthesis.

Antiparasitic Activity

Acridine derivatives show significant promise against protozoal infections:

Antimalarial activity

Compounds such as Quinacrine were historically used against malaria,^[18,21] acting by interfering with parasite DNA and heme detoxification pathways.

Fig. 4 : Correlation between DNA/HAS-interactions & antimalarial activity of acridine derivatives

Antileishmanial activity:

DNA intercalation and mitochondrial disruption mechanisms have been reported.^[19,29,30]

Antitrypanosomal activity:

Acridine analogues demonstrate inhibition of kinetoplast DNA replication.

Antiviral Potential

Certain acridine derivatives inhibit viral replication by targeting viral polymerases or interfering with nucleic acid processing. Investigations into broad-spectrum antiviral applications are ongoing.

Anti-inflammatory and Immunomodulatory Effects

Some acridine-based molecules exhibit modulation of cytokine production and immune signaling pathways, supporting their exploration in rare inflammatory and autoimmune conditions.

This pharmacological versatility makes the acridine nucleus a promising scaffold for drug development in rare and neglected diseases.

Table 1 :  Pharmacological activities of Acridine and its derivatives

ACRIDINE DERIVATIVES IN NEGLECTED TROPICAL DISEASES

Neglected tropical diseases (NTDs) remain a major public health concern in developing regions, disproportionately affecting economically disadvantaged populations. The World Health Organization has identified diseases such as malaria, leishmaniasis, and trypanosomiasis as priority conditions requiring improved therapeutic interventions. Limitations of current drugs—including resistance, toxicity, long treatment duration,^[33,34] and high cost—have encouraged renewed exploration of versatile heterocyclic scaffolds such as acridine.

Acridine derivatives demonstrate notable antiprotozoal activity primarily due to their planar   aromatic structure, which facilitates interaction with parasite DNA and key enzymatic systems. In malaria, acridine compounds interfere with nucleic acid synthesis and disrupt heme detoxification within the parasite’s food vacuole.^[20] The historical use of Quinacrine exemplifies the antimalarial relevance of this scaffold. Structural optimization strategies have since focused on improving selectivity toward Plasmodium species while minimizing host cytotoxicity.

In leishmaniasis and trypanosomiasis, acridine derivatives target kinetoplast DNA and mitochondrial function, leading to impaired parasite replication. Several synthetic analogues have demonstrated enhanced potency against drug-resistant strains, highlighting their potential in overcoming existing therapeutic limitations. Furthermore, hybrid molecules combining acridine with other bioactive pharmacophores have shown synergistic antiparasitic effects.^[35,36]

Beyond protozoal infections, emerging studies suggest that modified acridine derivatives may exhibit activity against drug-resistant tuberculosis and certain helminthic infections, though clinical validation remains limited. Toxicity, particularly related to DNA intercalation in host cells, remains a key challenge. Therefore, current research emphasizes selective targeting, nanoparticle-based delivery systems, and structure–activity refinement to enhance therapeutic indices.

Overall, the acridine nucleus represents a promising scaffold for the development of cost-effective and mechanistically diverse agents against neglected tropical diseases.

STRUCTURE–ACTIVITY RELATIONSHIP (SAR) STUDIES OF ACRIDINE DERIVATIVES

Understanding the structure–activity relationship (SAR) of acridine derivatives is essential for optimizing their therapeutic potential while minimizing toxicity. The biological activity of acridine-based compounds is highly influenced by substitution patterns, electronic properties, side-chain modifications, and hybridization with other pharmacophores.

The planar tricyclic acridine core is crucial for DNA intercalation. However, unsubstituted acridine often shows high cytotoxicity due to non-selective DNA binding. Therefore, modifications at specific positions—particularly the 2-, 4-, 6-, and 9-positions—have been widely explored^[4,5] to improve selectivity and pharmacological performance.

Substitution at the 9-position plays a critical role in modulating biological activity. For example, 9-aminoacridine derivatives exhibit enhanced DNA binding affinity^[20,25] and improved antiparasitic or anticancer activity. Side chains containing basic amines increase water solubility and promote electrostatic interaction with nucleic acids. However, excessive lipophilicity may increase nonspecific toxicity.

Scheme 4 : SAR of Acridine derivative as an anti-tumour agent

Scheme 5 : SAR of Acridine and its derivatives

Electron-donating or electron-withdrawing groups on the acridine ring influence π–π stacking interactions and binding strength with molecular targets such as topoisomerases. The clinically used anticancer agent Amsacrine demonstrates how strategic substitution enhances enzyme inhibition while maintaining therapeutic relevance.

In recent years, hybrid molecule design has gained importance. Acridine conjugated with other pharmacologically active moieties has shown improved target specificity, reduced resistance development, and enhanced potency in neglected tropical disease models.

Table 2 : Key SAR Modifications and Their Biological Impact

Overall, SAR studies indicate that careful structural tuning of the acridine nucleus can balance efficacy and safety. Future optimization strategies increasingly rely on computational modeling, molecular docking, and rational drug design approaches to develop selective acridine-based therapeutics.

TOXICITY AND SAFETY CONSIDERATIONS

Despite the promising pharmacological profile of acridine derivatives, their clinical application is often limited by safety concerns. The primary challenge arises from their planar aromatic structure, which enables strong DNA intercalation. While this property contributes to antimicrobial and anticancer efficacy, it may also result in non-selective interaction with host DNA, leading to cytotoxicity and genotoxic effects.^[31]

One of the major concerns associated with acridine compounds is mutagenicity. Prolonged or high-dose exposure may induce DNA damage, chromosomal aberrations, or interference with normal cell replication. These risks are particularly relevant in anticancer therapy, where DNA-targeting mechanisms are intentionally exploited. The therapeutic use of Amsacrine demonstrates that controlled dosing and structural optimization can help balance efficacy with manageable toxicity.

Fig 5 : Toxicological studies

Hepatotoxicity and gastrointestinal disturbances have also been reported with certain derivatives, including Quinacrine, especially during long-term administration. Additionally, nonspecific accumulation in healthy tissues due to lipophilic character may increase systemic side effects.

To address these limitations, modern research focuses on improving therapeutic indices through rational structural modification. Strategies include selective substitution to reduce non-specific DNA binding, development of hybrid molecules with enhanced target specificity, prodrug approaches, and nanoparticle-based drug delivery systems. Such approaches aim to direct acridine derivatives preferentially toward diseased cells or pathogens while minimizing host toxicity.

CLINICAL STATUS AND REGULATORY PERSPECTIVE

Although numerous acridine derivatives have demonstrated strong preclinical potential, only a limited number have progressed to clinical use.^[41]  Their advancement has largely depended on balancing therapeutic efficacy with manageable toxicity, particularly due to DNA-interacting properties.

One of the most notable clinically utilized acridine derivatives is Amsacrine, which has been employed in the treatment of acute leukemias. Its mechanism involves topoisomerase II inhibition combined with DNA intercalation, demonstrating how structural refinement of the acridine scaffold can yield clinically viable anticancer agents. Similarly, Quinacrine has historically been used as an antimalarial and has been investigated for repurposing in autoimmune and prion-related disorders.

From a regulatory standpoint, rare diseases receive special consideration under orphan drug frameworks. Agencies such as the U.S. Food and Drug Administration and the European Medicines Agency provide incentives including market exclusivity,^[39,40] tax credits, and accelerated approval pathways to encourage drug development for orphan indications. These provisions create opportunities for repositioning acridine-based compounds in rare disorders.

Fig. 6 : Drug Development

However, for neglected tropical diseases, regulatory and financial incentives are often more limited. Development frequently depends on global health initiatives and collaborations supported by organizations such as the World Health Organization. Clinical translation in this area requires demonstration of affordability, safety in long-term use, and effectiveness in resource-constrained settings.

Overall, while only a few acridine derivatives have achieved full regulatory approval, evolving orphan drug policies, repurposing strategies, and global health partnerships provide promising avenues for future clinical advancement.

FUTURE PERSPECTIVES AND RESEARCH DIRECTIONS

The acridine nucleus has consistently demonstrated versatility as a scaffold in drug discovery, yet significant opportunities remain for expanding its role in rare and neglected disease therapeutics. Future research is expected to focus on several key areas:

Rational Drug Design and Molecular Optimization

Advances in computational chemistry, molecular docking, and AI-driven drug design^[25,27] are enabling precise modifications of the acridine scaffold. These approaches aim to maximize target specificity, improve pharmacokinetics, and minimize off-target toxicity, particularly for DNA-interacting derivatives.

Hybrid Pharmacophores and Conjugates

Hybrid molecules combining acridine with other bioactive moieties can enhance potency and selectivity. For example, linking acridine to antimalarial, anticancer, or antimicrobial pharmacophores has shown synergistic effects in preclinical studies. This strategy may also help circumvent drug resistance, a common issue in neglected tropical diseases.

Nanotechnology and Targeted Delivery Systems

Encapsulation of acridine derivatives in nanoparticles, liposomes, or polymeric carriers can improve solubility, reduce systemic toxicity, and deliver drugs specifically to affected tissues or pathogens. Such delivery systems are particularly promising for diseases requiring prolonged treatment in vulnerable populations.

Drug Repurposing and Orphan Disease Applications

Given their established pharmacokinetic profiles, existing acridine derivatives can be strategically repurposed for rare diseases.^[32] Computational screening and phenotypic assays will accelerate identification of novel therapeutic indications while reducing development costs.

Clinical Translation and Global Health Focus

Collaboration between academic institutions, pharmaceutical companies, and global health organizations will be essential to translate preclinical findings into safe and affordable therapies. Regulatory frameworks, such as orphan drug designations and accelerated approval pathways, provide further incentives for development.

In summary, the combination of structural versatility, modern medicinal chemistry tools, and innovative delivery strategies positions acridine derivatives as promising candidates for addressing unmet medical needs in rare and neglected diseases.

Fig. 7 : Roadmap for Acridine Research