Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide [1,2]. The disease is characterized by the progressive decline of cognitive functions, including memory, language, and reasoning, significantly impacting patients' quality of life and that of their caregivers [3,4]. At the molecular level, AD is associated with an imbalance of two key enzymes: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). AChE is responsible for the hydrolysis of acetylcholine, a neurotransmitter essential for cognitive function, while BChE assists in the metabolism of acetylcholine and is increased in the more advanced stages of AD. Both enzymes have been implicated in the formation of amyloid-beta plaques [5].

The cholinergic hypothesis, which highlights the crucial role of acetylcholine in brain function, has driven the development of AChE inhibitors as the primary pharmacological approach to AD treatment [6,7,8]. Current FDA-approved drugs, such as donepezil and rivastigmine, selectively inhibit AChE, but their efficacy is limited and they often cause undesirable side effects [9,10]. Consequently, there is a growing interest in developing dual inhibitors targeting both AChE and BChE, which could provide a more effective and safer therapeutic strategy for AD [11].

Cholinesterase inhibitors can be classified into three categories based on their mechanism of action: reversible, irreversible, and pseudo-reversible. These classifications help to define their pharmacodynamic profiles and inform the development of therapeutic strategies, particularly for AD treatment. Reversible inhibitors (e.g., donepezil and galantamine) bind non-covalently to the catalytic site, offering transient inhibition, while pseudo-reversible agents, such as rivastigmine, form carbamyl-enzyme complexes that slowly hydrolyze. Irreversible inhibitors, such as organophosphates, covalently modify the active serine residue, leading to prolonged toxicity [12]. In particular, dual inhibitors targeting both AChE and BChE hold promise, as they may provide broader therapeutic effects by addressing both early and late stages of the disease. For instance, hybrid molecules like ladostigil and tacrine-coumarin conjugates exhibit balanced inhibition of AChE and BChE, counteracting the compensatory upregulation of BChE in advanced AD and reducing side effects linked to excessive AChE selectivity [13].

In the search for novel cholinesterase inhibitors, triazole and lactam moieties have garnered significant attention due to their diverse bioactivities. Triazole derivatives exhibit anti-inflammatory, antimicrobial, antifungal, and anticholinesterase properties [14,15,16], while lactam-containing compounds have demonstrated neuroprotective potential in AD models [17,18,19]. Notably, recent studies highlight triazole-based hybrids (e.g., tacrine-1,2,3-triazole derivatives) as multitarget ligands with nanomolar potency against both ChE isoforms, synergizing cholinergic modulation with antioxidative effects [20].

Moreover, several natural products and synthetic derivatives containing these structural motifs have shown inhibitory activities against AChE and BChE, supporting their potential therapeutic application in AD [21,22]. However, despite their individual significance, no hybrid molecules combining both moieties have been explored for AD therapy, presenting a novel and promising avenue for drug discovery.

Examples of clinically used drugs incorporating these moieties (Fig. 1) include Apixaban (a lactam-based anticoagulant), Banzel (a triazole-containing anticonvulsant), and Ribavirin (a triazole-based antiviral) [23,24,25]. Additionally, Piracetam [26], one of the most extensively studied nootropic drugs, further supports the pharmacological relevance of lactam-containing compounds.

Although Piracetam is not a direct cholinesterase inhibitor, its cognitive-enhancing effects are attributed to its modulation of the cholinergic system, specifically by increasing the density of acetylcholine receptors on neuronal membranes, thereby enhancing cholinergic neurotransmission [27]. This indirect influence on acetylcholine signaling suggests that lactam moieties can contribute to neuroprotective and cognitive-enhancing properties, making them valuable scaffolds in the design of novel AChE and BChE inhibitors.

Given the proven therapeutic importance of these structural frameworks, the incorporation of fluorine atoms into the design of new molecules represents a key strategy in drug development. Fluorine significantly modifies the pharmacokinetic and pharmacodynamic properties of bioactive compounds [28,29]. The high electronegativity of fluorine and the stability of the CF bond contribute to enhance the metabolic stability by blocking sites susceptible to enzymatic oxidation, thereby prolonging their half-life and therapeutic effect [30]. Additionally, fluorination modulates lipophilicity, a crucial parameter in drug absorption and distribution, optimizing membrane permeability without compromising bioavailability [31]. Another critical advantage of fluorine incorporation is its ability to improve target protein binding affinity, either through direct interactions with receptors or by altering the polarity and conformation of adjacent functional groups [32]. Notably, approximately 20 % of currently marketed pharmaceuticals contain at least one fluorine atom in their structure, highlighting the strategic importance of fluorine in drug optimization. These properties have led to the widespread use of fluorinated compounds across various therapeutic classes, including anticancer, neuroactive, and anti-inflammatory agents [33]. In this context, the strategic incorporation of an aryl‑fluorine moiety into our proposed structures aims to capitalize on these advantages, enhancing the stability, permeability, and efficacy of the designed compounds.

Building upon the pharmacological significance of the aforementioned structural motifs, we have designed and synthesized novel triazole-lactam hybrid compounds (Fig. 2) as potential dual inhibitors of AChE and BChE. Thus the integration of a lactam ring into the triazole core, along with the strategic incorporation of fluorine, is intended to enhance the pharmacological profile of these molecules by improving their binding affinity, selectivity, and metabolic stability. This approach represents a new and unexplored chemical space for Alzheimer's disease drug development.

In the context of AD drug discovery, green chemistry methodologies and nanocatalyst-based approaches have emerged as efficient tools for the synthesis of bioactive compounds. The triazole moiety is widely recognized for its biological relevance and click chemistry- which was awarded the Nobel Prize in Chemistry in 2022- provides an efficient and environmentally friendly synthetic route for triazole-containing molecules [34,35]. Recent advancements in green synthetic methodologies have enabled the development of eco-friendly strategies for triazole synthesis. In our research, we employ heterogeneous metal nanoparticle-based catalysts to enhance both reaction efficiency and sustainability. In recent years, we have designed copper-based nanocatalysts [36], including unsupported copper nanoparticles [37] (CuNPs) and copper nanoparticles supported on activated carbon [38,39] or zinc oxide (ZnO) [40]. These catalysts have enabled us to carry out highly selective click chemistry reactions for the synthesis of 1,2,3-triazoles, which hold significant potential in medicinal chemistry [41,42,43].

In summary, by integrating green chemistry principles with nanocatalyst systems, our work contributes to both sustainable synthetic methodologies and the development of novel bioactive compounds for potential AD therapy [44]. This approach aligns with the core principles of green chemistry by minimizing waste and reducing the environmental impact of drug synthesis, while simultaneously addressing key challenges in medicinal and industrial chemistry. Our research aims to establish a model for the sustainable development of innovative therapeutics, expanding the chemical space for potential AD treatments while adhering to environmentally responsible synthetic strategies.