Molecular insights into triazole-based compounds for triple-negative breast cancer treatment

Ahamed Vilangalil, Sindhu Priya E S, Sarad Pawar Naik Bukke, Sandhya V, Nafeesa Meha, Chandrashekar Thalluri, Kasolo Daniel, Allan Amooti Ahikiriza

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking oestrogen, progesterone, and HER2 receptors, thus limiting the effectiveness of targeted therapies. Triazole compounds have emerged as promising anticancer agents because of their structural versatility, chemical stability, and ability to interact with multiple biological targets. This review summarises the chemistry, biological significance, and therapeutic potential of triazole derivatives against TNBC. It highlights key anticancer mechanisms, including apoptosis induction, cell cycle arrest, inhibition of angiogenesis and metastasis, and modulation of major oncogenic signalling pathways. The review also compares synthetic and naturally derived triazole compounds, emphasising structure–activity relationships and evidence from preclinical studies. In addition, it discusses the contribution of computational approaches, including molecular docking, virtual screening, and predictive modelling, to accelerate triazole-based drug discovery. Overall, this review underscores the potential of triazole pharmacophores as effective therapeutic candidates for TNBC and provides directions for future research to overcome therapeutic resistance.
GRAPHICAL ABSTRACTDiagram illustrating triazole derivatives, their anti-tumor mechanisms against breast cancer, computational approaches, and future directions. The multi-panel diagram presents triazole derivatives with a detailed molecular structure, emphasizing their stability, versatility, and interaction with biological targets. The anti-tumor mechanisms are highlighted, including apoptosis induction, cell cycle arrest, angiogenesis inhibition, metastasis suppression, and oncogenic signaling modulation. Computational approaches like molecular docking and virtual screening are included, alongside insights into triple negative breast cancer (TNBC), noting the absence of hormone receptors and outlining potential treatment advancements with triazole derivatives.[IENZ_A_2732821_UF0001_C.webp][IENZ_A_2732821_UF0001_C.gif]

Introduction

Overview of triple-negative breast cancer (TNBC)

Triple negative breast cancer (TNBC) is a distinct and aggressive type of breast cancer in which there is no expression of oestrogen receptors (ER), progesterone receptors (PR), or human epidermal growth factor receptor 2 (HER2). This lack of hormone receptors reduces the efficacy of targeted hormonal therapy and HER2-directed therapy and contributes to the aggressive nature of triple-negative breast cancer. It accounts for about 10–15% of all breast cancer cases and is more common in younger women, especially those with mutations in the Breast Cancer Gene-1 (BRCA1). This disease is characterised by rapid growth of tumours, early metastasis, and a higher recurrence rate than other breast cancer subtypes.

Triple-negative breast cancer has a high molecular diversity, which poses challenges to understanding its biology and developing effective therapies,. Unlike hormone receptor-positive breast cancer, triple-negative breast cancer does not have a single therapeutic target, which makes chemotherapy the current standard of care. Research has identified several triple-negative breast cancer subtypes, including basal, mesenchymal, and immunomodulatory subtypes, each with different molecular characteristics and therapeutic potentials (). Ongoing efforts to classify triple-negative breast cancers based on genomic and transcriptomic data are essential to identify new therapeutic objectives and treatment approaches for individual patients.

Triple-negative breast cancer is associated with poor prognosis and limited treatment options. Although progress in immunotherapy and targeted therapy has been made, the disease remains difficult to treat, particularly in cases of metastatic disease. Despite initial response to chemotherapy, triple-negative breast cancer patients often relapse as drug resistance develops. Therefore, there is an urgent need to discover and develop new molecular therapies to improve the outcome of patients with this aggressive form of breast cancer.

Current treatment strategies and their limitations

The primary treatment approach for triple-negative breast cancer is usually a combination of surgery, chemotherapy, and radiotherapy. Neoadjuvant chemotherapy, given before surgery, is a common strategy for reducing the size of tumours and facilitating breast cancer surgery. Then, adjuvant chemotherapy is often used to remove any remaining cancer cells. However, the lack of targeted treatment options for triple-negative breast cancer often leads to poor long-term results. While traditional chemotherapeutic agents such as anthracyclines and taxanes remain the backbone of TNBC therapy, they are often associated with serious systemic toxicity and have a poor survival profile in patients with metastatic disease. The intrinsic and acquired resistance to these drugs is a major problem, leading to recurrence and progression of cancer. The lack of predictive biomarkers also makes it difficult to select the most effective treatment regimen for each patient.

In recent years, immune checkpoint inhibitors (ICI) targeting programmed death ligand 1 (PD-L1) have emerged as promising therapeutic modalities, especially in patients with high levels of expression of targeting programmed death ligand 1 (PD-L1). A combination of immune checkpoint inhibitors with chemotherapy has, in some cases, improved progression-free survival. However, not all patients with TNBC respond to immunotherapy, which highlights the need for additional biomarkers to predict response and to optimise treatment strategies.

Poly(ADP-ribose) polymerase (PARP) inhibitors are an important class of targeted therapy for the treatment of breast cancer, particularly tumours harbouring germline BRCA1+ mutations or other homologous recombination (HR) defects. PARP inhibitors such as Olaparib and Talazoparib exploit faulty homologous recombination repair in breast cancer, BRCA1+ mutated, by inhibiting DNA repair mediated by PARP and trapping PARP in damaged DNA resulting in DNA accumulation, replication fork collapse, and synthetic lethality.

The heterogeneity of TNBC continues to hamper efforts to develop drugs. Subtype-specific approaches are currently being explored, including targeted inhibitors of key signalling pathways such as PI3K, AKT, MTOR, and JAK-STAT. These targeted therapies have the potential to improve clinical outcomes by providing a personalised approach to TNBC treatment. However, the lack of validated biomarkers and emergence of resistance mechanisms make it difficult to translate them clinically, which further highlights the urgent need for innovative therapeutic strategies.

The therapeutic landscape for advanced TNBC has expanded substantially with the development of alternative therapy products. Sacituzumab govitecan is a trop-2 antibody consisting of a Trop-2-directed antibody that is associated with the SN-38 topoisomerase-I inhibitor. It delivers its cytotoxic payload primarily to tumour cells expressing Trop-2, followed by intracellular release of SN-38 and inhibition of topoisomerase I, resulting in DNA damage and death of tumour cells. Notably, in June 2026, the FDA expanded the role of TNBC by approving sacituzumab govitecan as first-line monotherapy in patients with unresectable locally advanced or metastatic TNBC and in combination with pembrolizumab in first-line PD-L1-positive disease (CPS >10). In addition, in May 2026, the FDA approved datopamab deruxtecan, another Trop-2-directed ADC, for the treatment of unresectable or metastatic TNBC in patients who are not candidates for PD-1 or PD-L1 inhibitors.

PARP inhibitors are a molecularly targeted treatment strategy in patients with germline BRCA1+ mutations and HER2 negative breast cancer. Olaparib and Talazoparib inhibit the repair mediated by PARP and induce PARP binding, thereby increasing DNA damage. Tumour cells with defective homologous recombination repair, in particular those containing alterations of the BRCA1 or BRCA2 family, are particularly sensitive to this mechanism. Olaparib is approved by the FDA as adjunctive therapy in patients with deleterious or suspected deleterious BRCA-mutated HER2 negative germline breast cancer at high risk of developing early breast cancer after neoadjuvant chemotherapy. Talazoparib is also an approved PARP inhibitor in the treatment of HER2-negative, locally advanced or metastatic breast cancer in patients with germline BRCA mutations. Conventional chemotherapy, including taxanes, anthracyclines, platinum compounds, capecitabine, gemcitabine, and related agents, remains an important component of TNBC treatment, particularly for patients ineligible for biomarker-directed therapies.

The need for novel molecular therapeutics

Given the aggressive nature of triple-negative breast cancer and the limited treatment options, it is urgent to identify and develop new molecular therapeutics. Unlike hormone receptor-positive breast cancer, TNBC lacks targeted therapies, leading to chemotherapy-based treatment, which often leads to drug resistance and major side effects. Innovative therapeutic approaches are necessary to address these challenges by selectively targeting the biological pathways that are involved in the growth, metastasis, and resistance mechanisms of tumours. Precision medicine strategies, including the identification of relevant genetic mutations and the development of targeted inhibitors, have the potential to transform the landscape of triple-negative breast cancer treatment.

Emerging therapies such as small-molecule inhibitors, antibody conjugates, and immunotherapies are being investigated to provide safer and more effective alternatives. In addition, rational drug design using computational methods has accelerated the discovery of new compounds with strong anticancer activity. Natural and synthetic small molecules, including triazole derivatives, have been shown to modulate key signalling pathways implicated in TNBC progression. Combining these new therapies with existing treatments can enhance their effectiveness, reduce resistance, improve patient outcomes, and offer a more comprehensive approach to TNBC treatment. Given the aggressive nature of TNBC and the limited treatment options, it is urgent to identify and develop new molecular therapeutics. Targeting key signalling pathways, inhibiting tumour proliferation, and inducing apoptosis are key strategies in the quest for more effective therapies. In this context, small-molecule inhibitors and bioactive compounds with selective cytotoxicity against TNBC cells have received considerable attention.

Triazole-based compounds in breast cancer therapy

Triazole derivatives, in particular 1,2,4-triazoles and 1,2,3-triazoles, have been identified as promising candidates for the development of anticancer medicines. Their unique chemical structure provides a broad range of binding capacities, enabling effective interactions with diverse biological targets. Triazole compounds have shown significant anti-tumour activity by means of mechanisms including inhibition of enzymes, deoxyribonucleic acid (DNA) intercalation, and disruption of key cellular pathways. Triazole derivatives have favourable pharmacokinetic properties, increased stability, and reduced toxicity, which contribute to their therapeutic potential. Recent research has highlighted the potential of triazole derivatives as selective inhibitors of triple-negative breast cancer proteins and offers a promising avenue for the development of targeted therapies for the treatment of breast cancer.

One of the main mechanisms by which triazole derivatives exert an anticancer effect is through inhibition of enzymes critical to tumour cell proliferation. For example, certain triazole compounds target kinases and proteases, thereby disrupting the signalling pathways involved in the growth and metastasis of tumours. In addition, triazoles have been shown to induce apoptosis by interfering with mitochondrial function and activating the caspase pathway. Such multi-targeted approaches increase their therapeutic effectiveness and reduce the likelihood of developing resistance to the product.

The hydrophilic-lipophilic balance of triazole compounds can be fine-tuned to optimise their uptake and distribution within the cell. Structural changes, including the insertion of specific functional groups, were used to enhance the selectivity and efficacy of triazole derivatives against TNBC cells. This adaptability makes them versatile candidates for combination therapies and may overcome resistance to conventional chemotherapy. Triazole derivatives have shown promising results in in-vitro and in-vivo against TNBC in recent studies. Molecular docking and in silico studies have identified triazole-based inhibitors targeting key proteins such as PARP, EGFR, and PI3K, which are often overexpressed in TNBC. Triazole derivatives have synergistic effects in combination with immunocompetent inhibitors and chemotherapy, further enhancing their clinical potential.

In view of the growing understanding of triazole chemistry and its use in cancer therapy, research continues to investigate new derivatives with greater specificity and reduced side effects. The integration of computational drug design, bioassays, and structural-activity relationship (SAR) analysis will be key to the successful development of triazole-based TNBC therapeutics. By progressing through preclinical and clinical trials, these compounds offer a promising route to improving patient outcomes and represent a much-needed addition to the existing TNBC treatment landscape .Triazole derivatives, in particular 1,2,4-triazoles and 1,2,3-triazoles, have been identified as promising candidates for the development of anticancer medicines. Their unique chemical structure provides a broad range of binding capacities, enabling effective interactions with diverse biological targets. Triazole compounds have shown significant anti-tumour activity by means of mechanisms including inhibition of enzymes, DNA intercalation, and disruption of key cellular pathways. In addition, their favourable pharmacokinetic properties, increased stability, and reduced toxicity contribute to their therapeutic potential. Recent research has highlighted the potential of triazole derivatives as selective inhibitors of TNBC proteins and offers a promising avenue for the development of targeted therapies for the treatment of tumours.

Nonsteroidal aromatase inhibitors such as letrozole, anastrozole, and vorazole () are widely used as anti-cancer agents, especially in hormone-positive breast cancer. These compounds belong to the triazole group and act by reversibly binding to the aromatic enzyme CYP19A1, which inhibits the conversion of androgens (androstenedione and testosterone) to oestrogens. By significantly reducing circulating oestrogen levels, they reduce the growth and spread of tumours that depend on oestrogens. Letrozole and anastrozole are clinically approved third-generation inhibitors, and vorozole has demonstrated strong activity in preclinical and clinical studies. Their high selectivity, oral bioavailability, and favourable safety profile make them an essential component of endocrine therapy, particularly in postmenopausal women with breast cancer.

Triazole-containing medicinal products constitute an important class of clinically identified heterocyclic medicinal products, with 1,2,4-triazole being particularly relevant for antifungal, anticancer, and other medicinal product applications. Several marketed medicinal products contain triazole pharmacophores, including Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isoflavimazole, Letrozole, and Anastrozole. The bioavailability of the triazole ring is due to its aromatic and electron-rich nature, the number of nitrogen atoms capable of hydrogen bonding, and its ability to engage in π-π interactions, hydrophobic interactions, and interactions with dipole groups with biological targets. The incorporation of a triazole moiety may increase target affinity, metabolic stability, water solubility, and overall pharmacological activity, and additional lipophilic groups in itraconazole and Posaconazole increase hydrophobic interactions and broaden the spectrum of the antifungal agent. Voriconazole maintains the basic interaction between triazoles and CYP51 but incorporates a fluoropyrimidine group, which contributes to its increased activity against several clinically important fungi.

Triazole pharmacophores are also important in the development of anticancer drugs, particularly for inhibiting steroidogenic enzymes. Both Letrozole and Anastrozole, which are non-steroidal aromatase inhibitors, contain a 1,2,4-triazole ring and inhibit CYP19A1, an enzyme involved in the conversion of androgens to oestrogens. The nitrogen in triazole coordinates with the haem iron in aromatase, thereby inhibiting oestrogen biosynthesis and reducing the proliferation of breast cancer cells dependent on oestrogen. Their SAR shows that the 1,2,4-triazole ring acts as a basic pharmacophore for metal binding. At the same time, the well-positioned nitrile or substituted aromatic groups enhance hydrophobic interactions at the active site of aromatase. The presence and location of aromatic rings are therefore important for maintaining potency, while substitution may affect lipophilicity, selectivity, and pharmacokinetic behaviour. The importance of the triazole nucleus in aromatase inhibitors has also spurred the development of numerous novel triazole derivatives targeting steroidal and cancer-related targets.

Aromatase-inhibitory 1,2,4-triazole derivatives have been shown to inhibit a variety of cancer-related mechanisms, including inhibition of tyrosine kinases such as EGFR and VEGFR, modulation of PI3K and STAT signalling, inhibition of carbonic anhydrase and topoisomerases, inhibition of tubulin dynamics, apoptosis and autophagy, and interference with DNA-dependent processes. Recent reviews suggest that structural optimisation of 1,2,4-triazoles usually involves N-substitution, incorporation of aryl or heteroaryl, modification of the linkers, fusion with other heterocycles, and molecular hybridisation. Electron-withdrawing groups, such as halogens and nitriles, may enhance hydrophobic or electronic interactions, while electron-donating groups in appropriate positions may enhance hydrogen-bonding interactions and electronic complementarity. Hybridisation of the triazole ring with pharmacophores such as quinazoline, pyridine, indole, thiadiazole, and other heterocyclic systems frequently produces greater anticancer activity than the corresponding monocyclic structures.

Traded triazole medicinal products provide valuable guidance and SAR principles for the rational design of new triazole derivatives for cancer. The central triazole ring provides a pharmacophore that is metabolically stable, polar, and aromatic, and rich in interactions. In contrast, modifications to peripheral aromatic groups, hydrophobic substituents, hydrogen-bond donors and acceptors, and molecular linkers may adjust potency, selectivity, and pharmacokinetic properties. In particular, the metal-binding capacity of the triazole nitrogen makes the scaffold attractive to enzymes containing haem or metal centres, and its ability to engage in multiple noncovalent interactions facilitates the identification of targets for kinases and other tumour-associated enzymes. Recent literature confirms that 1,2,4-triazole derivatives are still under investigation against EGFR, VEGFR, aromatase, STAT, PI3K, and other molecular targets, supporting their potential as a versatile scaffold for the development of next-generation anti-cancer agents, including candidates for breast cancer and TNBC.

Although several reviews and compendia have described the medicinal chemistry and pharmacological uses of triazole derivatives, this review is unique in that it specifically addresses breast cancer, in particular, triple-negative breast cancer. Most reviews have mainly provided a broad overview of 1,2,4-triazole-containing compounds in different therapeutic areas or discussed their general anticancer potential without systematically highlighting the molecular mechanisms specific to breast cancer. This review integrates the chemical structures, structural and activity relationships, molecular targets, mechanisms of action, and therapeutic relevance of triazole derivatives specifically for breast cancer. Particular emphasis is placed on clinically relevant targets and pathways associated with breast cancer, including aromatase (CYP19A1), EGFR, HER2, PI3K/Akt, PARP1, VEGFR, and apoptosis-related signalling pathways. The review further distinguishes itself by comparing marketed triazole-containing drugs with investigational triazole derivatives, thereby demonstrating how established pharmacophores can guide the design of novel anticancer candidates.

To the best of our knowledge, no previous review has comprehensively integrated breast cancer-specific SAR, molecular mechanisms, validated and emerging targets, marketed triazole-containing medicinal products, computational approaches, and recent experimental evidence on triazole derivatives, with particular relevance to TNBC. This review, aims to fill this gap by providing a targeted pharmaceutical chemist’s perspective on breast cancer treatments based on triazole.

Triazole chemistry and its biological relevance

Structural features of triazole compounds

Triazoles are five-membered heterocyclic compounds with two carbon atoms and three nitrogen atoms. They are mainly found in two isomeric forms: 1,2,3-triazoles and 1,2,4-triazoles (), each of which has a unique electronic structure and chemical reactivity. These isomers are noted for their high nitrogen density, stability within aromatic structures, and ability to engage in hydrogen bonding and coordination, making them important pharmacophores in medicinal chemistry. The difference between 1,2,3 and 1,2,4 triazoles provides a different electronic and physical arrangement of the ring nitrogens, and the ultimate anti-cancer activity is controlled by the interaction of this heterocyclic nucleus with the substituents and their respective pharmacodynamic structure. The synthesis of 1,2,3-triazole derivatives has progressed considerably with the development of catalytic oxidation of click compounds, particularly the copper(I)-catalyzed azide cycloaddition (CuAAC). This reaction, independently discovered by Sharpless and Meldal in the early 2000s, allows the formation of 1,4-disubstituted triazoles. The reaction is well tolerated under mild conditions, is tolerant of a wide range of functional groups, and affords high yields with minimal by-products, making it a preferred strategy for the synthesis of triazole-linked molecules in the fields of medicinal chemistry, materials science, and chemistry.

The synthesis of 1,2,4-triazole derivatives is predominantly achieved through cyclisation of hydrazide, thiosemicarbazide, amidrazone, or related nitrogen-rich precursors. A widely used synthetic sequence involves converting carboxylic acids or esters to the corresponding hydrazides with hydrazine hydrate, followed by treatment with carbon disulphide and a base to generate dithiocarbazate intermediates. Subsequent cyclisation under acidic or oxidative conditions affords 1,2,4-triazole-3-thione derivatives, which can be further functionalised to generate diverse analogs. Alternatively, thiosemicarbazides can undergo cyclocondensation with carboxylic acids or their derivatives, while condensation of hydrazides with aldehydes followed by oxidative cyclisation provides another versatile route to substituted 1,2,4-triazoles. These methodologies permit modification at different positions on the heterocyclic ring and are therefore particularly valuable for structure–activity relationship studies. Microwave-assisted cyclisation has further improved synthetic efficiency by reducing reaction times and, in several cases, increasing product yields. The choice of synthetic route depends on the desired substitution pattern, precursor availability, reaction conditions, and the physicochemical properties of the target triazole derivative.

Modern synthetic strategies also investigate multi-component reactions (MCRs) and non-metallic protocols for triazole formation. MCR enables rapid assembly of triazole frameworks from simple precursors in one pot, thereby increasing efficiency and molecular complexity. Transition metal-free conditions, such as thermal azide-alkyne cycloaddition or organocatalytic reactions, are becoming increasingly attractive for green chemistry applications. The wide range of synthetic methods, from classical to advanced, continues to expand the chemical space of triazole derivatives, making it easier to develop new drugs and materials.

Structurally, the triazole rings serve as bioisosteres for amides, esters, and other heterocycles, enabling them to replace the labile groups of lead compounds without compromising their bioactivity. Their high electron density and ability to participate in π-π stacking and dipole interactions enable them to bind efficiently to a variety of biological targets, such as enzymes, receptors, and nucleic acids. In addition, triazoles resist hydrolytic and oxidative degradation, which improves the pharmacokinetic profile of triazole-containing medicinal products.

Mechanistic diversity of triazole derivatives

Mechanistically, triazole derivatives exhibit different modes of action depending on the mode of substitution and the nature of the scaffold. They have been shown to inhibit enzymes such as cytochrome P450 enzymes, histone deacetylases (HdA), and carbonic anhydrase (CA). For example, the rings of 1,2,4 triazole in antifungal agents such as fluconazole and voriconazole bind to the iron haem in the 14-demethylase of the fungal enzyme lanosterol 14a, thereby interfering with the biosynthesis of ergosterol and cell membrane integrity.

Triazoles also have a broad range of biological activities, including anticancer, antimicrobial, antiviral, anti-inflammatory, and anticonvulsant properties. Their anti-tumour potential is particularly remarkable, as they may act as kinase inhibitors, DNA intercalators, and inducers of apoptosis. The ability to fine-tune their electronic and steric properties by substitution makes them adaptable to a wide range of biological targets, increasing their selectivity and efficacy. In cancer, triazole-based inhibitors have shown promise against multiple molecular targets, including PI3K receptors, EGFR, and oestrogen receptors. These targets are involved in pathways regulating the cell cycle, proliferation, and angiogenesis. The modular nature of triazole synthesis allows for rapid optimisation of the lead compounds and facilitates structural relationship analysis studies, which are essential for the development of anticancer drugs.

Role of triazoles in drug development

In terms of drug development, triazoles make a significant contribution to the design of hybrid molecules and drug conjugates. Their chemical compatibility with a variety of binders and carriers makes them ideal for prodrug strategies, nanoparticle delivery systems, and antibody conjugates. Moreover, the triazole-based binding is stable under physiological conditions, thereby reducing the risk of early drug release or degradation. Several FDA-approved medicines contain triazole rings, which highlights their therapeutic value. Remarkable examples include antifungal drugs (fluconazole, itraconazole), HIV medicines (rilpivirine), and cancer drug candidates under study. These successes highlight the versatility of triazoles not only in traditional small-molecule drugs but also in more complex therapeutic platforms, such as targeted therapies and immunomodulators.

Recent studies have reported the formation of hybrid triazole-estradiol compounds that target the epidermal growth factor receptor (EGFR), a receptor often overexpressed in TNBC. The active substances are designed to inhibit EGFR signalling, which is associated with proliferation, migration, and poor prognosis in patients with TNBC. Among these compounds, B () demonstrated potent cytotoxic activity against T-lymphocyte cell lines, including MDA-MB-231 and MDA-MB-468, with an IC5 in the low-micromolar range. These triazole derivatives not only block the activity of EGFR but can also modulate downstream pathways such as PI3K, AKT, and MAPK, thereby increasing their therapeutic potential.

3–(34,5-trimethyloxyphenyl)-5-(N-methyl-3-indolel)-1,2,4-triazole (NMK-T-057) is a promising multi-drug candidate for the treatment of breast cancer, as it inhibits the signalling pathway of the cytochrome P450 system via the enzyme called notch. Its ability to inhibit proliferation, migration, EMT and stem formation while inducing apoptosis by autophagy, together with its potent anti-tumour activity in the murine 4T1 model, highlights its therapeutic potential to target the secretase-notch axis in TNBC. Importantly, its limited cytotoxicity to non-cancer cells further supports its potential for further preclinical development in the future. The multifunctional potential of triazoles was also investigated in hybrid molecules that combine the triazole ring with other pharmacophores, such as histone deacetylase (HDAC) and PARP inhibitors, thereby increasing potency and tolerance to resistance. Taken together, these findings show that triazole-containing molecules represent a promising class of compounds for the targeted treatment of TNBC, and ongoing efforts are being made to improve their selectivity, efficacy, and drug-like properties.

The development of triazole-containing medicinal products has been further supported by advances in computational modelling and molecular docking. These tools enable the prediction of binding affinity and the visualisation of triazole interactions with protein targets, thereby improving the efficacy of drug discovery. Machine learning approaches have also begun to predict biological activity from triazole substituents, thereby accelerating lead optimisation. The triazole chemistry offers a solid framework for drug development, due to its synthetic availability, structural versatility, and broad range of biological activity. Its integration into modern medicinal chemistry continues to expand, spurred by innovations in synthetic methods and computational tools. Strategic inclusion of triazoles in therapeutic products is a powerful approach in the ongoing search for safer and more effective medicinal products.

Molecular mechanisms of triazole-based compounds in TNBC

Targeting cell proliferation and growth pathways

Triazole compounds have been shown to interfere with the uncontrolled proliferation of TNBC cells by targeting growth-regulatory signalling pathways. One of the primary mechanisms is inhibition of tyrosine kinase receptors such as EGFR, which is commonly overexpressed in TNBC. These receptors trigger a cascade that increases transcription of genes involved in cell division. By blocking the activation of receptors or downstream effects such as PI3K and mTOR, triazoles interfere with mitogenic signalling required for TNBC cell proliferation. Triazoles have been shown to impair the activity of cyclin-dependent kinases (CDKs), particularly CDK4 and CDK6, which regulate G1 cell cycle progression. This inhibition reduces retinoblastoma (Rb) protein phosphorylation, thereby preventing the release of E2F transcription factors required for entry into S phase. As a consequence, TNBC cells are blocked in the G1 phase and are unable to proceed with DNA synthesis and replication.

Triazole compounds frequently interfere with transcription factors, such as c-Myc, which regulate genes involved in cell metabolism and proliferation. Downregulation of c-Myc and suppression of the mTOR pathway not only reduces protein synthesis but also reduces the overall bioavailability of TNBC cells, thereby impairing their ability to grow and divide under the stress of the tumour microenvironment.

Apoptosis induction and cell cycle modulation

The triazole-based molecules induce apoptosis in TNBC cells primarily by an intrinsic mitochondrial pathway. This mechanism involves disruption of the potential of the mitochondrial membrane, resulting in cytochrome c release and activation of caspase-9, followed by caspase-3 and −7. Triazoles modulate the balance of proteins in the Bcl-2 family by downregulating the anti-apoptotic (Bcl-2, Bcl-xl) and pro-apoptotic (Bax) proteins, and tipping the balance towards cell death.

.Triazoles activate the extrinsic apoptotic pathway by activating death receptors such as FAS and TRAIL-R. Activation of these receptors initiates the caspase-8 cascade, which may either directly activate downstream caspases or potentiate the mitochondrial apoptotic pathway. This dual-pathway activation enhances the efficacy of triazole-induced apoptosis, especially in aggressive TNBC subtypes resistant to monotherapy. Another critical effect of triazole derivatives on TNBC is the modulation of the cell cycle. These compounds may induce arrest at various cell cycle checkpoints, including G0, G1, and G2. This is achieved by inhibiting cyclin expression (e.g. cyclin D1 and cyclin B1) and activating checkpoint kinases such as p21 and p27. Arresting the cell cycle halts TNBC proliferation and predisposes cells to apoptosis, particularly when combined with DNA-damaging or other cytotoxic agents.

Anti-angiogenic and anti-metastatic properties

Triazole compounds have been shown to inhibit angiogenesis, a key process in tumour survival and spread. These molecules inhibit the expression of vascular endothelial growth factor (VEGF), a key mediator of tumour blood vessel growth. Reduced levels of VEGF reduce endothelial cell recruitment and the formation of new blood vessels, effectively depriving the tumour of oxygen and nutrients that are necessary for it to continue to grow and metastasise. In addition, triazoles target matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, which degrade the extracellular matrix and facilitate TNBC cell invasion and metastasis. By inhibiting the expression of MMP and enzyme activity, triazole compounds reduce cell invasion via the basement membrane and reduce the TNBC cells’ ability to metastasise to distant organs such as the lungs and liver.

The triazole derivatives also affect epithelial-mesenchymal transition (EMT), which is a key process in the metastatic cascade. These compounds upregulate epithelial markers, such as E-cadherin, and downregulate mesenchymal markers, such as vimentin and N-cadherin. This reversal of EMT prevents the TNBC cells from acquiring the characteristic migratory and invasive characteristics of the tumour, thereby preventing its spread from the primary site of tumour. These anti-metastatic effects significantly increase the therapeutic potential of triazoles in the treatment of aggressive and metastatic TNBC.

1,2,3-Triazole derivatives are an important class of cancer-fighting triazole compounds, since the three adjacent nitrogen atoms provide a polarised aromatic scaffold for hydrogen bonding and dipole-mediated interactions with biological targets. Their activity may be significantly altered by the presence of aryl, hetero-aryl, steroidal or other pharmacophore groups around the ring of the triazole. For example, the estradiol-linked derivatives B, C and D () exhibited cytotoxic activity against MDA-MB-231 T-cells with IC5 values of 8.12 ± 0.85, 21.18 ± 0.23 and 10.86 ± 0.69 mg, respectively. These compounds also showed activity against MDA-MB-468, with IC5 of 25.43 ± 3.68 mg for B. Mechanistic studies have shown interference of EGFR-related signalling and of the downstream ERK and MTOR pathways, accompanied by cell cycle arrest and apoptosis induction. These findings demonstrate that incorporation of the 1,2,3-triazole ring into a steroidal framework can generate compounds capable of modulating growth-factor signalling relevant to TNBC.

The anticancer potential of 1,2,3 triazoles is highly dependent on the nature and the position of the substituents attached to the heterocyclic nucleus of the molecule. 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol (A) reported to have an IC5 of approximately 0.074 micrograms against MDA-MB-231 cells, demonstrating the considerable potency achievable through appropriate pharmacodynamic optimisation ( and ). Compared to less active analogs, incorporating suitable aromatic and hydrophobic substituents may increase molecular complementarity with the target binding site, and adding hydrogen-bonding groups may strengthen interactions between the ligands and the protein. Similarly, the estradiol-triazole derivatives B and D were more active against MDA-MB-231 than C, indicating that substitutions, hydrophobicity, conformational orientation, and electronic properties of the active substance influence cellular potency. Thus, the 1,2,3-triazole ring should be considered a versatile pharmacophoric and linker unit rather than an independent determinant of anticancer activity.

In contrast, 1,2,4 triazoles contain nitrogen atoms at 1, 2 and 4 positions, resulting in a different electronic distribution and hydrogen bonding geometry than the isomer 1,2,3 triazole. This structural difference may significantly impact target recognition and biological activity. Diatabolite derivatives of 1,2,4-triazole compounds E () showing IC5 values of 17 micrograms against MDA-MB-231 cells. Structural modifications of aryl substituents have affected the antiproliferative response, with a clear correlation between substitution patterns and activity. Other 1,2,4-triazole compounds have been designed to interact with cancer enzymes and signalling proteins, including EGFR, HER2, PI3K, PARP1, and aromatase. The 1,2,4-triazole scaffold provides a useful platform for developing structurally diverse compounds directed towards molecular pathways involved in TNBC proliferation, survival, invasion, and apoptosis.

Further structural diversification was achieved by combining 1,2,4-triazole with other pharmacophores such as indole, thiadiazole, aryl, and Schiff base moieties. Such hybridisation may increase the molecular rigidity, increase the π-conjugation, introduce additional hydrogen bonding sites, and improve the interaction with the target protein’s hydrophobic regions. For example, indole-linked 1,2,4-triazole (F) showed an IC5 of approximately 48.22 mg/ml against MDA-MB-231 cells after 48 h of treatment (). Mechanistic studies have linked its activity to inhibition of focal adhesion kinases (FAK and PTK2) accompanied by cell cycle arrest and apoptosis in the G1 phase. The compound also demonstrated anti-migratory effects, which are particularly relevant to TNBC due to its aggressive and metastatic phenotype. These observations show how combining a triazole nucleus with another bioactive heterocycle can alter bio-profiling and yield effects beyond simple cytotoxicity, including modulation of signalling, proliferation, migration, and apoptosis.

Although a number of triazole derivatives have shown promising in-vitro activity against TNBC cell lines, relatively few compounds have been evaluated in-vivo. Therefore, available evidence should be differentiated at the experimental level, including computational modelling, in vitro cytotoxicity, mechanistic assays, and animal studies. For example, indole-1,2,4-triazole 4c has been further evaluated in preclinical studies, including in vivo toxicity and tolerability, which support its potential for further development. However, compounds such as A, B, and D () should be considered promising experimental candidates, particularly if their evidence is limited to cellular studies. The comparison of 1,2,3 and 1,2,4 triazole derivatives suggests that the anti-tumour activity is determined not only by the triazole isomer but also by the complete molecular structure, including the heterocyclic nucleus, the substituents, the aromatic and hydrophobic groups, the molecular bonding, and other pharmacophores. Therefore, future developments should integrate structural and activity relationships, target-based studies, pharmacokinetic evaluation, toxicity assessment, and in vivo efficacy to identify triazole derivatives with real translational potential against TNBC.

Interaction with key oncogenic pathways

PI3K/akt pathway

Triazole compounds exert anti-cancer effects in triple-negative breast cancer (TNBC) by targeting the phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) signalling pathways, which are often hyperactivated by PI3K mutations and by loss of the phosphatase and tensin homolog (PTEN). By inhibiting phosphatidylinositol-3-kinase (PI3K) or preventing the phosphorylation and activation of Protein Kinase B (AKT), triazole derivatives inhibit downstream signalling pathways, including the mechanistic target of rapamycin (mTOR), the transcription factor glycogen synthase-3 beta (GSK-3 beta), and the forkhead-box O (FOXO) transcription factors. This disruption reduces glucose metabolism, protein synthesis, and signalling pathways involved in cell survival, ultimately decreasing cell viability and increasing susceptibility to apoptotic stimuli in triple-negative breast cancer (TNBC).

NF-κB pathway

In triple-negative breast cancer (TNBC), triazole compounds also modulate the nuclear factor of kappa light chain (NF-κB) signalling pathway, which is critical for inflammation, cell survival, and resistance to apoptosis. These compounds inhibit the activity of IκB kinase (IKK), thereby preventing the phosphorylation and subsequent breakdown of the Kappa B-alpha inhibitor (IκB-alpha). As a result, nuclear factor of kappa light chain enhancer of B cells (NF-κB) remains in the cytoplasm, preventing its nuclear translocation and the transcription of survival and anti-apoptotic genes. Suppression of this pathway increases apoptotic signalling and contributes to decreased chemoresponsiveness in triple-negative breast cancer (TNBC).

MAPK pathway

In triple-negative breast cancer (TNBC), triazole compounds also affect the mitogen-activated protein kinase (MAPK) signalling pathway, which includes extracellular signal-regulated kinases 1 and 2 (ERK1 and 2), c-Jun N-terminal kinase (JNK), and p38 MAPK, and is a critical pathway for cell proliferation and apoptosis. These compounds inhibit mitogenic signalling by blocking phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), leading to reduced proliferation and cell-cycle arrest. At the same time, some triazole derivatives activate mitogen-activated protein kinase p38 (MAPK) or inhibit c-Jun N-terminal kinase (JNK) activity, thereby shifting signalling dynamics towards pro-apoptotic responses. By modulating multiple MAPK pathways in a coordinated fashion, triazoles disrupt the survival signalling networks and promote programmed cell death in triple-negative breast cancer (TNBC) ().

Triazole derivatives as potential therapeutic agents for TNBC

Synthetic and natural triazole-based molecules

Synthetic triazole derivatives have been extensively studied in cancer applications, including the treatment of triple-negative breast cancer (TNBC). Medicinal chemists have developed a number of scaffolds for 1,2,3 and 1,2,4 triazoles containing different aryl, hetero-, and alkyl substitutions that increase cytotoxicity against TNBC cells. For example, compounds containing a fused triazole and thiadiazole backbone have a high selectivity against MDA-MB-231 cells due to mitochondrial dysfunction and inhibition of the polymerisation of microtubules.

An important synthetic example is triazole conjugated chalcone, which combines two bioactive moieties. In TNBC lines, these hybrids demonstrated potent cytotoxicity by targeting tubulin polymerisation and inducing G2/M cell cycle arrest. The dual action of chalcone and triazole units leads to increased efficacy, demonstrating the potential of a rational hybrid design for the treatment of TNBC. A second category includes quinoline analogs bound to triazole, which have been shown to reduce the viability of TNBC cells by inhibiting topoisomerase II and modulating DNA damage response proteins. These compounds often have excellent drug-like properties such as metabolic stability and favourable lipophilicity, which support their systemic use.

Synthetic triazoles have been incorporated in multi-target cancer medicines in addition to monotherapy agents. HDAC inhibitors containing a triazole have been shown to reprogram epigenetic markers in TNBC cells, reversing silencing of tumour suppressor genes and increasing apoptotic signalling. These multi-functional formulations demonstrate the adaptability of triazoles as a key pharmacophore. Natural triazole compounds, although less common, have been isolated from marine and fungal sources and exhibit mild antiproliferative activity. Triazolopyrimidines from marine mushrooms, for example, have shown promising anti-TNBC activity. Although the number of natural triazoles is limited, they have been an inspiration for the development of semi-synthetic analogs with increased potency and specificity.

Exploration of structure-activity relationships

SAR studies have played a key role in optimising triazole derivatives for the treatment of TNBC. These studies systematically modify the substituents on the triazole ring or on the adjacent linkages to determine their effects on bioactivity. For example, electron-withdrawing groups such as nitrosides and halogens in the para-position of the phenyl ring attached to triazole often increase cytotoxic potency by increasing cell permeability and potentiation of target binding. Changes in the alkyl chain that connects the triazole ring to other pharmacophores also revealed significant trends in the SAR. Short, flexible linkers tend to favour improved cellular uptake and interaction with enzyme targets, while rigid or thickened chains may impair the enzyme’s bioavailability. In HDAC-triazole inhibitors, in TNBC models, the optimal length of the binding domain was critical to maintain zinc binding and maximise enzyme inhibition.

SAR analysis of triazole-conjugated steroids showed that substitution patterns at the D-ring influence the selectivity for hormone-independent breast cancer cells. This is especially useful for TNBCs that lack hormone receptors. The addition of polarised side chains improved water solubility and reduced off-target toxicity, which was a common problem for early synthetic lead formulations. Other areas of research in the field of SAR were heterocyclic systems fused or attached to a triazole nucleus. Triazole-benzimidazole hybrids and triazole-thiazole hybrids often show increased activity in the inhibition of DNA intercalation or kinase. These two pharmacologically active substances have synergistic effects that enhance cytotoxicity against aggressive TNBC cells while minimising the impact on normal mammary epithelial cells.

.SAR data are now supported by in situ methods such as molecular docking and pharmacodynamic modelling. These approaches have sped up the identification of lead triazole compounds in TNBC that target PI3K, BRD4, or tubulin. Computational results help refine synthetic strategies, shorten synthesis time, and provide predictive models of compound efficacy across various preclinical TNBC models.

Preclinical evidence and experimental models

Triazole compounds have shown potent anti-neoplastic activity in various preclinical models. In vitro tests using TNBC cell lines, such as MDA-MB-231, BT-549, and HS5-1957, demonstrated that triazole derivatives can significantly reduce cell viability, induce apoptosis, and inhibit migration. These effects are often quantified by means of MTT, Annexin V, and PI stains or wound healing tests.

Animal studies have further confirmed the anti-tumour efficacy of triazole compounds. For example, xenograft models implanted in immunodeficient mice with MDA-MB-231 cells showed reduced tumour volume when treated with triazole-based PI3K inhibitors. Pharmacokinetic evaluations in preclinical models were also performed to evaluate the bioavailability, half-life and tissue distribution of triazole compounds in mice, which demonstrated both efficacy and safety in vivo. Many derivatives exhibit favourable oral absorption and a moderate plasma half-life, making them suitable for possible oral use. Stability in vivo is often enhanced by structural modifications such as N-methylation and esterification.

Histopathological examination of tumour tissues from treated animals often reveals increased apoptosis, decreased angiogenesis, and decreased proliferation markers such as Ki-67. These findings correlate with biochemical changes as detected by Western blotting, including decreased Akt and NF-κB signalling, which confirm the physiological activity of the compounds in a physiological setting. In addition to xenografts, patient-derived tumour organoids and 3D spheroids are increasingly used to test the efficacy of triazoles. These advanced models provide a more realistic picture of tumour architecture and drug uptake profiles, and offer valuable translational insights. Several triazole candidates showed promising results in these models, which supported their progress to formal toxicity and IND-enabling studies.

Computational approaches in triazole drug discovery for TNBC

Molecular docking, molecular dynamics, and virtual screening

Molecular docking has become an important structural approach for identifying and optimising triazole derivatives against molecular targets involved in triple-negative breast cancer (TNBC). Rather than being used only to rank compounds by docking score, docking may provide a structural explanation for why specific substituents or hybrid scaffolds enhance biological activity. EGFR is of particular relevance as it is often overexpressed in TNBC and is an important therapeutic target. This approach provides structural information on ligand-target interactions and allows prioritisation of molecules with high binding values for synthesis and bioassays. For example, a study in 2023 used AutoDock Vina to assess a library of pyridines bound to triazole and to identify the top hits with nanomolar affinity to Akt1.

The recent example is the design of the estradiol-1,2,3-triazole analogs Fz25, Fz57, and Fz200 as TNBC agents dependent on EGFR. Molecular docking against EGFR (PDB: 1M17) and molecular dynamics analysis supported a favourable interaction of the triazole scaffold in the EGFR binding region. Importantly, the calculations were supplemented with experimental data: Fz25 showed IC50 values of 8.12 ± 0.85 and 25.43 ± 3.68 mg against MDA-MB-231 and MDA-MB-468, respectively. These compounds inhibit EGFR and the downstream signalling pathways ERK and MTOR, and induce cell cycle arrest and apoptosis. Docking and molecular dynamics thus not only predicted binding but also helped promote the structure of estradiol-1,2,3-triazole as a new EGFR-directed scaffold for TNBC.

.Recent advances in docking have included flexible modelling of ligands and receptors, thereby increasing the accuracy of predictions for dynamic targets commonly found in TNBCs. Software such as Schrödinger’s Glide and Gold now offers induced-fit protocols that capture more accurate conformational changes in target proteins upon ligand binding. This is particularly useful for triazole compounds, where the presence of multiple rotational bonds may affect binding orientation and efficacy.

.In 2024, a hybrid 1,2,3-triazole[1,2,4]triazole[3,4-b][1,3,4]thiadiazine was developed via a chemical conjugation strategy and evaluated as an EGFR-targeted anticancer drug. The molecular docking and ADMET analyses were integrated, and compounds 7f and 7h demonstrated superior in vitro anticancer activity relative to erlotinib, along with potent EGFR inhibitory activity. The relevance of this strategy is that the computational analysis supported combining two heterocyclic pharmacophores rather than the traditional single triazole ring. Such a scaffold fusion may increase molecular rigidity, increase aromatic surface area, and create additional hydrogen-bonding and hydrophobic interactions, thereby providing new chemical structures for targeted cancer detection.

Molecular docking may also be combined with experimental SAR to determine the structural parameters responsible for the enhanced TNBC activity. A recent series of indole-1,2,4-triazole hybrids is a good example. These compounds have been designed by binding to substituted 1,2,4-triazoles and have been tested against MDA-MB-231 cells and EGFR-TK (PDB: 1M17). Compound 4i, containing halogen substituents on indole and phenyl rings, showed the most potent antiproliferative activity, with an IC50 of 2,121 micrograms against MDA-MB-231. The docking results supported a favourable interaction with EGFR, and an ADMET analysis was conducted to evaluate the drug-likeness of the analogue. This example shows how computational analysis can guide the selection of electronically and hydrophobically optimised substituents, ultimately yielding a more effective chemical structure.

Virtual screening of compound libraries has enabled the high-throughput identification of novel triazole compounds with potential anti-TNBC properties. Databases such as ZINC, PubChem, and CHEMBL were scanned in silico against targets relevant to TNBC. The 2024 screening campaign identified a number of kinase inhibitors containing triazole with selective activity against TNBC cell lines by binding to the ATP binding site of PAK1, a known regulator of TNBC invasion.

For triazole derivatives, fragment-based virtual screening was also used. Researchers break down the lead triazole compounds into smaller pharmacophores, attach them individually, and then recombine the most promising fragments. This approach has resulted in the rational design of bidentate inhibitors that occupy two functional pockets on the protein surface simultaneously, an approach that increases both selectivity and efficacy for TNBC targets. In addition, docking studies are now integrated with pharmacodynamic modelling to determine the structural parameters necessary for binding to TNBC targets. The pharmacodynamic model based on known EGFR triazole inhibitors in TNBC was helpful for the virtual screening and led to the identification of new scaffolds with favourable docking scores and in vitro validation. These integrative methods streamline the pipeline of discovery and reduce reliance on expensive experimental testing.

In silico ADMET profiling and optimization of drug-like properties

In silico, the ADMET (absorption, distribution, metabolism, excretion and toxicity) profile is essential to assess the drug-like properties of triazole derivatives in TNBC. Tools such as SwissADME, pkCSM and ADMETLAB 2.0 allow scientists to predict physicochemical properties, oral bioavailability, intracellular permeability and cytochrome P450 inhibition. This helps to exclude triazole compounds with adverse pharmacokinetics at an early stage of the discovery. The series of Fz25, Fz57, Fz200 estradiol-1,2,3 triazole, where only Fz25 was reported to have a completely satisfactory in silico profile for ADMET.Fz25 was therefore the most promising compound for further computational and biological investigation, demonstrating how the ADMET filter can narrow the list to a more feasible candidate rather than selecting compounds solely for their cytotoxicity.

.Recent studies have shown that many triazole derivatives meet the Lipinski Rule of Five criteria, indicating good oral bioavailability. However, some analogs exhibit high lipophilicity or poor solubility, which can be optimised by adjusting the polarity or introducing solubilising groups. A 2023 report optimised triazole-thiourea hybrids for TNBC by reducing logP values while maintaining target affinity, resulting in improved oral absorption predictions. Predicting toxicity is another key element in in silico profiling. ADMET models now provide predictions for hepatotoxicity, cardiotoxicity (e.g. inhibition of the hERG channel), and genotoxicity. One study used ADMET Predictor to refine a number of triazole-related flavonoids, excluding those with high anticipated hepatic toxicity, thereby increasing the likelihood of clinical translatability. Triazole derivatives are frequently metabolised by CYP3A4, and computational tools can predict their metabolic sites and stability. This allows medicinal chemists to design analogs that are less susceptible to rapid degradation or formation of toxic metabolites.

A recent series of indole-1,2,4-triazoles illustrates this approach, in which structural changes, including halogen substitutions, were evaluated experimentally for MDA-MB-231 activity and calculated for EGFR and ADMET binding. Compound 4q, which included halogen substitution in both aromatic regions, exhibited increased cellular activity, suggesting that computationally supported structural diversification may contribute to the identification of a more favourable lead architecture. Plasma protein binding (PPB) and volume of distribution (Vd) predictions are useful for predicting in vivo pharmacokinetic behaviour. ADMET profiling has shown that some triazole derivatives exhibit high PPB, potentially decreasing the drug’s free concentration. Optimisation of the molecular weight and hydrophobic surface area has helped to improve these properties in recent triazole candidates for TNBC that have undergone preclinical evaluation.

QSAR, machine learning and AI-assisted triazole design

QSAR and machine learning approaches offer further opportunities to move from qualitative SAR observations to quantitative predictions of biological activity. Molecular descriptors such as molecular weight, logP, topological polar surface area, hydrogen bonding capacity, molecular volume and electronic parameters may be correlated to experimentally determined anticancer activity to determine structural properties related to efficacy. Although studies on AI targeting only triazoles against TNBC are still relatively limited, computational studies combining QSAR, docking, ADMET and molecular dynamics have demonstrated the potential of this integrated approach. For example, recent studies of drug discovery in breast cancer used QSAR models to identify physicochemical descriptors that affect activity, and then combined these predictions with docking and MD simulations to prioritise compounds. Such a workflow is particularly valuable for triazoles, as the substitution pattern can vary widely, creating large chemical spaces that are difficult to investigate experimentally.

Recent work has used deep learning frameworks, such as graph convolutional networks (GCNs), to represent triazole molecules as graphs, enabling highly reliable bioactivity prediction against TNBC targets. For example, a study in 2024 used GCN to screen thousands of triazole compounds and to predict EGFR inhibitors, which were subsequently confirmed in vitro using TNBC cell lines. AI and ML should be presented in the review as an emerging approach, rather than as evidence that large-scale trial candidates of triazole TNBC generated by AI have already been extensively tested.

Computer methods have contributed to the discovery of triazole drugs for TNBC in two main ways: optimisation of existing pharmacophores and generation of new chemical structures. Docking identifies target binding site regions that may contain substituents, MD simulations assess the stability of these interactions, and ADMET predictions exclude candidates with adverse drug-like properties. This information may then be transferred to structural modifications such as 1,2,3-triazole-estradiol hybrids, 1,2,4-triazole-indole hybrids, triazole-schiff base systems and fused structures of triazole-thiadiazole. The recent example of estradiol-1,2,3 triazole is particularly compelling as computational analyses supported EGFR binding and favourable ADM characteristics, and experimental studies subsequently demonstrated cytotoxicity and inhibition of EGFR and ERK and MTOR signalling in TNBC. Similarly, the development of hybrids of 1,2,3-triazole and triazolothiazide shows how computational scaffold fusion can generate structures with increased EGFR targeting potential.

Reinforcement learning (RL) and generative adversarial networks (GANs) are used to create new triazole molecules with optimum properties. These models can learn from the desired outcomes (e.g. low toxicity, high target affinity) and propose improved candidates for further iteration. In addition, an AI-based study in late 2023 generated triazole hybrids with multiple target activities against both PI3K and mTOR, which were synthesised and shown to inhibit TNBC cell growth with minimal toxicity. These platforms shall use ADMET predictive models, synthetic feasibility and target binding. Combining AI with cloud-based synthesis-planning tools enable the automated generation and evaluation of compounds, thereby shortening the discovery time for triazole-based TNBC therapies.

Explainable AI (XAI) tools such as SHAP (Shapley Additive Explanation) and LIME (local interpretable model-agnostic elucidation) are used to understand which triazole molecular structures are most responsible for activity or toxicity. This feedback loop helps to improve the design principles and to increase confidence in the compounds generated by the artificial arm for TNBC treatment.

Computational approaches are useful for the design and optimisation of triazole derivatives, but docking scores and predicted ADMET profiles are not a direct determinant of therapeutic efficacy. The highly anticipated target binding may not translate into cellular activity due to poor permeability, efflux, metabolic instability, or toxicity. A series of erlotinib derivatives containing 1,2,3-triazole rings was designed using a structure-based method and combined with deep learning drug-target interaction models to predict their affinities. The derivatives were synthesised and tested for their IDO1 inhibitory activities. The results indicated that the activities of some compounds were better than those of erlotinib. Computational findings should be supported by synthesis, in vitro cytotoxicity, mechanistic studies, and in vivo evaluation. Machine learning and generative artificial intelligence can further optimise potency, selectivity, pharmacokinetic properties, and synthetic feasibility, but experimental validation is still necessary to confirm the anticancer potential of triazole derivatives developed computationally.

Triazole derivatives in combination therapy for TNBC

Triazole derivatives, once known for their excellent antimicrobial and antifungal properties, have now taken on a new role as effective anticancer agents due to their structural diversity and favourable pharmacokinetic profiles. These molecules have anti-tumour activity via multiple mechanisms, including inhibition of cell growth, induction of apoptosis, inhibition of angiogenesis, and regulation of intracellular signalling pathways. In TNBC - an aggressive type of breast cancer without receptors for oestrogen, progesterone, or HER2 - the combination of triazole derivatives in combination therapies has been shown to be significant. Chemoresistance, which is often seen in TNBC, remains a major barrier to clinical oncology. Conventional chemotherapeutic agents such as doxorubicin, paclitaxel, and cisplatin remain the mainstay of TNBC treatment, but their efficacy is often compromised by drug resistance and off-target toxicity. Triazole derivatives in combination with these anticancer medicines also showed synergistic anti-tumour activity, resulting in increased tumour cell killing and improved therapeutic efficacy.

Synergistic effects with chemotherapeutics and targeted therapies

Triazole derivatives have the potential to increase apoptosis induction by increasing the pro-apoptotic activity of chemotherapeutic agents by altering mitochondrial pathways, increasing the Bax-Bcl-2 ratio and activating caspases. For example, some 1,2,3 triazole hybrids have been shown to sensitise TNBC cells to doxorubicin by increasing depolarisation of the mitochondrial membrane and increasing activation of caspase-3. Increased uptake and intracellular retention of some triazole derivatives have been shown to involve interactions with cell membrane transport proteins or modulation of cell membrane permeability, thereby increasing intracellular concentrations of anticancer agents. This is especially important in TNBC cells, which frequently over-recycle efflux pumps such as P-glycoprotein (P-gp), reducing the bioavailability of the drug. These derivatives can modulate DNA repair and ROS production, thereby interfering with tumour cell DNA repair mechanisms and making them more sensitive to DNA-damaging agents such as cisplatin. In addition, these compounds may increase reactive oxygen species (ROS) production, pushing cancer cells beyond their oxidative stress threshold and triggering apoptosis. In combination with conventional chemotherapy, triazole compounds have shown potential to interfere with the targeted therapy, particularly in drug-resistant TNBC models. For example, in BRCA-mutated TNBC, poly (ADP-ribose) polymerase inhibitors such as Olaparib are used, but resistance may arise from recombination recovery or increased drug efflux. Triazole-based compounds could target the compensatory mechanism or affect epigenetic modulators, thereby sensitising the tumour to PARP inhibition.

Triazole derivatives have shown promise as co-treatments with epidermal growth factor receptor (EGFR) inhibitors, such as gefitinib. EGFR is highly overexpressed in TNBC and has a poor prognosis. Few triazole analogs exhibit inherent EGFR-inhibitory activity or can be hybridised with identified EGFR-targeting moieties, yielding dual-action compounds that inhibit proliferation and survival signalling pathways. These actions usually converge on cell-fate-determining nodes, such as the PI3K/Akt/mTOR and NF-κB pathways, which control survival, growth, and chemoresistance in TNBC. Compound Fz25, in particular, showed strong potency and favourable drug-like properties, supporting its further development for combination regimens. Benzothiazole-triazole hybrids arrested the cell cycle and induced apoptosis in TNBC cells, primarily by inhibiting Bcl-2. This suggests they could develop chemotherapeutic agents that target apoptotic pathways more effectively. Triazole-estradiol analogs have also been shown to kill TNBC cell lines by blocking EGFR and its downstream pathways. This suggests they could be more effective when combined with other EGFR-targeted therapies or chemotherapeutics. Triazole-tethered boswellic acid derivatives exhibited potent anti-proliferative activity, with some compounds outperforming their parent molecules. These derivatives may act synergistically with other agents by targeting CHK1, a key regulator in cancer cell survival.

Benzene sulphonamide- bearing bis-1,2,3-triazole derivatives 102 showed a significant cytotoxic effect, with an IC50 value of 1.81 μM, against breast cancer cell lines (MDA-MB231). 1,2,3-Triazoles containing sulphonamide moieties 103 and 104 showed significant anticancer activity against the MCF-7 cancer cell line, with IC50 values of 12.4 and 23.4 μM, respectively, compared to the standard drug doxorubicin ().

Overcoming drug resistance in TNBC

The current problem in the treatment of TNBC is the onset of multidrug resistance (MDR), a process that seriously undermines the efficacy of chemotherapeutic and targeted drugs. In contrast to other subtypes of breast cancer, TNBC has no clear-cut hormonal or HER2 targets, leading to the use of non-specific cytotoxic agents. The rate of recurrence and lack of good long-term survival, though, are mainly a result of the rapid drug resistance acquired by the tumour. The azole ring binds to transporter protein domains, preventing substrate binding or ATP hydrolysis. By inhibiting drug efflux, triazoles render resistant TNBC cells sensitive to standard chemotherapy and lower the required dose, reducing systemic toxicity. Cancer stem cells (CSCs), which can self-renew and have intrinsic resistance to treatment, also underlie TNBC recurrence and resistance.

Blocking drug efflux pumps

Various triazole derivatives have been reported to inhibit P-glycoprotein, thereby restoring intracellular levels of chemotherapeutic agents such as doxorubicin or paclitaxel. The azole ring binds to transporter protein domains, preventing substrate binding or ATP hydrolysis. Through inhibiting drug efflux, triazoles make resistant TNBC cells sensitive to standard chemotherapy and lower the dosing required for therapy, reducing systemic toxicity.

Targeting survival pathways and resistance-associated kinases

Some 1,2,3-triazole-linked hybrids, for instance, have been designed to inhibit EGFR and Akt, two kinases that are frequently hyperactive in TNBC. These dual inhibitors disrupt downstream survival signals and induce apoptosis, even in cells previously resistant to monotherapy. Triazole derivatives also regulate critical oncogenic pathways linked to drug resistance. Inhibition of NF-κB, a transcription factor implicated in inflammatory and anti-apoptotic gene regulation, has been found with some triazole analogs ().

Interfering with cancer stem cell (CSC) and tumor microenvironment signaling

Triazole-based agents can interfere with cancer stem cell (CSC) signalling pathways, including Notch, Wnt/β-catenin, and Hedgehog, that are involved in tumour relapse and drug resistance. Triazole derivatives may reduce the likelihood of resistance development by blocking several drug-resistance pathways, such as EGFR, Bcl-2, and CHK1, when used in combination with traditional treatments. Triazole scaffold-derived LPA1 antagonists inhibit TNBC cell invasion and migration but not cytotoxicity, offering a novel means to prevent metastasis and overcome drug resistance to conventional cytotoxic agents. Certain triazole derivatives are anti-inflammatory or anti-angiogenic, acting indirectly on TME-mediated resistance.

Synthetic hybrids for dual action

Rational drug design has led to the synthesis of hybrid molecules containing triazole moieties tethered to known kinase inhibitors, histone deacetylase (HDAC) inhibitors, or tubulin-targeting compounds. The conjugates have additive or synergistic effects by targeting two resistance mechanisms simultaneously. Triazole-based dual EGFR-Akt inhibitors, for instance, have shown potential to overcome resistance in TNBC cells by inhibiting kinase phosphorylation and inducing DNA damage responses, in combination with DNA-damaging drugs. Triazole derivatives inhibit several pathways involved in drug resistance, including EGFR, Bcl-2, and CHK1, thereby reducing the likelihood of resistance development when administered alongside conventional therapies. LPA1 antagonists derived from triazole scaffolds suppress TNBC cell invasion and migration but not cytotoxicity, providing an innovative way to inhibit metastasis and overcome resistance to traditional cytotoxic drugs.

Potential for personalized medicine

TNBC is characterised by high molecular and phenotypic heterogeneity. This heterogeneity highlights the limitation of uniform treatment strategies and calls for personalised medicine. Precision or personalised medicine designs therapeutic interventions according to an individual’s characteristic genetic, molecular, and phenotypic tumour signature. In this shifting paradigm, derivatives based on triazole hold significant promise as chemotypes, with versatility and the potential to be structurally optimised to a particular patient’s needs.

Chemical flexibility and modular design

One of the most essential features of triazole scaffolds is their chemical flexibility. The stable, bioactive 1,2,3-triazole ring, often formed via click chemistry, connects pharmacophores. This modularity makes it easy to quickly design a wide range of triazole-based molecules with different physical and chemical properties and biological activities.

Target particular oncogenic mutations

Act selectively against overexpressed transporters or enzymes, including P-glycoprotein or cytochrome P450 isoforms. React to microenvironmental signals such as hypoxia, acidosis, or inflammation within the tumour microenvironment. Such structural versatility places triazole derivatives as prime candidates for designing tailored therapeutics in TNBC.

In silico modeling and biomarker-based targeting

Recent computational drug design advances have enabled the identification and optimisation of triazole compounds based on individual patients’ biomarkers. Researchers can use molecular docking, QSAR modelling, and machine learning to predict how certain triazole derivatives will interact with target proteins in a patient’s tumour. This enables identification of the best compound or combination based on the patient’s proteomic and mutational profile. For example, docking simulations have shown that some triazole-spaced kinase inhibitors bind very well to mutant EGFR or Akt proteins, which are common in some TNBC subpopulations. In the same way, BRCA-mutated patients can be given PARP inhibitors as a top priority, making treatment even more personalised.

Delivery systems for targeted nanocarriers

Encapsulating triazole agents in nanocarriers like liposomes, solid lipid nanoparticles, or polymeric micelles can make them more selective and less toxic to the whole body. The carriers can be modified with targeting ligands that specifically bind to tumour surface markers. These include Folate-conjugated systems for tumour cells overexpressing folate receptors.

CD44-targeted carriers to bind to cancer stem cells: Transferrin or integrin-based ligands for receptor-mediated uptake. The ligand-guided targeting strategy enables drug-carrying nanocarriers to target cancer cells while avoiding normal tissues, a fundamental principle of individualised medicine. Furthermore, the surface chemistry of the nanocarriers can be engineered to be responsive to environmental stimuli, such as pH or redox gradients, so that the drug is delivered only to the tumour site.

Integration with omics data and clinical decision tools

Genomic, transcriptomic, and proteomic information obtained from patient biopsies can inform the rational selection of triazole compounds or delivery systems. For instance, tumours with hypoxic gene expression signatures might respond to triazole derivatives that release reactive oxygen species only when oxygen is scarce. AI-powered clinical decision support systems can match these molecular signatures to libraries of structurally diverse triazoles, speeding up the planning of precise treatment.

Challenges and future perspectives

Pharmacokinetics and toxicological considerations

One of the main limitations of triazole derivatives in TNBC treatment is their unpredictable pharmacokinetics. Despite promising results in vitro, many candidates have poor systemic exposure due to insufficient solubility or rapid clearance. Challenges such as suboptimal gastrointestinal absorption, limited bioavailability, and high first-pass metabolism prevent them from advancing to clinical candidates. Addressing these issues requires formulation strategies such as nanoparticle encapsulation, prodrug design, or moiety incorporation to increase permeability.

Toxicological liabilities remain a major concern during lead optimisation. Although triazoles are generally considered metabolically stable, some analogs may form reactive intermediates or accumulate in non-target tissues, leading to adverse effects. Studies have shown hepatotoxicity and hematological concerns with some triazole analogs, especially when administered at high doses. A comprehensive safety evaluation, including long-term toxicity and immunogenicity studies, is required before these agents enter clinical trials.

The possibility of drug interactions complicates the use of the medicinal product, especially in patients receiving multiple therapies. Triazole compounds may inhibit or induce the activity of key cytochrome P450 enzymes, thereby affecting the metabolism of concomitantly administered medicinal products. The development of analogs with a reduced enzyme interaction profile or the use of combination therapy with careful monitoring may alleviate these problems, and early toxicogenomic profiling may help to predict and minimise unexpected adverse reactions.

Translational challenges from bench to bedside

A major translational barrier is the discrepancy between preclinical efficacy and clinical performance. Triazole compounds that show potent anti-TNBC activity in vitro often fail to replicate these results in animal models or human studies due to differences in the tumour microenvironment, the immune response, and the compounds’ pharmacodynamics. This divergence highlights the need for more predictive in vivo models, such as patient-derived xenografts (PDX) and humanised mouse models, to characterise the biology of human tumours better.

.Regulatory barriers also play an important role in slowing the journey from bench to bedside. Novel triazole-based substances require extensive documentation, including synthesis, stability, pharmacology, and safety data. Due to the structural novelty of many triazole scaffolds, additional testing is often required, particularly in the first human studies. The lack of prior human use of many triazole derivatives may prolong the preclinical phase and delay entry into clinical use. Another key barrier is the design of clinical trials for TNBC, which is a highly heterogeneous and aggressive subtype of breast cancer. Patient stratification by molecular markers is critical but often underused in early-phase studies. Triazole compounds may only have an effect in specific subpopulations of TNBC, such as those with PI3K pathway activation or EGFR overexpression. The inclusion of companion diagnostics and biomarker-based selection criteria may significantly increase the likelihood of clinical success.

Future directions in triazole-based TNBC treatment

In the future, the therapeutic potential of triazole derivatives in TNBC may be enhanced by integrating multi-target strategies. Designing compounds that simultaneously inhibit kinases, epigenetic regulators, and immune checkpoints could yield synergistic effects. Researchers are increasingly investigating triazole hybrids that may modulate multiple pathways involved in TNBC progression, including immune evasion and DNA repair defects. This multi-target approach may overcome resistance mechanisms and increase response durability.

Emerging technologies such as artificial intelligence-guided drug design, 3D bioprinting of tumour models, and high-throughput organ-on-chip systems are poised to revolutionise the development of triazole drugs. These platforms allow rapid prototyping and real-time feedback on efficacy, toxicity, and pharmacokinetics. Combined with CRISPR-based genetic screening, these may help identify patient-specific deficits and match triazole scaffolds to different treatment regimens.

Conclusion

Triazole-based compounds have emerged as a promising class of anticancer agents for the investigation and potential treatment of triple-negative breast cancer (TNBC), owing to their structural versatility and diverse biological activities. Mechanistic studies suggest that selected triazole derivatives may modulate key oncogenetic signalling pathways, including PI3K, AKT, NF-κB, and MAPK, and may induce apoptosis and cell cycle arrest. In addition, several triazole compounds have been shown to have anti-angiogenic and anti-metastatic effects by inhibiting VEGFR and VEGFR-like signals, matrix metalloproteinases, and epithelial-mesenchymal transitions. These multi-target effects are particularly relevant in TNBC, which is characterised by significant molecular diversity, aggressive behaviour, drug resistance, and the limited availability of targeted therapies. Both synthetic and naturally inspired triazole derivatives have shown promising preclinical activity against TNBC cell models, but their potency, molecular targets, and mechanisms vary depending on the chemical scaffold and substitution pattern. Importantly, despite encouraging in vitro findings, the relatively limited in vivo validation of triazole compounds in TNBC models remains a major translational gap. Further structure–activity relationship studies, target validation, pharmacokinetic and toxicity investigations, and well-designed in vivo efficacy studies are therefore required to facilitate the development of triazole-based candidates into clinically relevant TNBC therapeutics.

Despite their biological promise, the translation of triazole derivatives from laboratory research into clinical use remains a challenge. Challenges include optimising pharmacokinetic properties, ensuring safety profiles, and resolving discrepancies between in-vitro and in-vivo efficacy. However, advances in computational modelling, including virtual screening, ADMET profiling, and the use of artificial intelligence, are helping to streamline drug discovery processes. SAR studies continue to inform rational modifications to increase selectivity and potency, and preclinical models, such as patient-derived organoids and xenografts, provide a more accurate platform for testing efficacy.

Integrating precision medicine approaches, multi-target design, and predictive biomarkers will be key to unlocking the full therapeutic potential of triazole compounds in TNBC. Cross-disciplinary cooperation and innovative technologies can help overcome translation hurdles and accelerate clinical development. As research continues to deepen our understanding of TNBC biology and triazole pharmacology, these compounds should contribute significantly to the development of new targeted therapies for this aggressive and currently underused subtype.

Funding Statement

The author(s) received no specific funding for this work.

Disclosure statement

All authors report that there was no conflict of interest in this work.

Availability of data and materials

Not applicable (this manuscript does not report data generation or analysis).