Alzheimer's Disease (AD) was first discovered and reported by a German doctor in 1906 [1]. It is the most common neurodegenerative disease and the leading cause of mortality in the world, representing around 70 % of the cases of neurodegeneration [2]. AD is biologically defined as β-amyloid-containing plaques and tau-containing neurofibrillary tangles [3], [4]. Neuronal injury and death are exacerbated by this aberrant protein accumulation and misfolding [5]. Furthermore, neuronal damage can be caused by oxidative stress [6], neuroinflammation [7], metal ion abnormalities [8], and low levels of improperly deposited acetylcholine [9].

According to the 2018 CE Epidemiology Report, nearly 50 million people worldwide suffer from AD. The number of people with dementia worldwide is expected to increase to more than 152 million by 2050 as the population ages. In the United States alone, the annual cost of treating dementia may exceed $600 billion [10]. The symptoms of memory impairment in early patients are mainly manifested as easy forgetting of recent events and memory impairment [11]. As the patient's condition worsens, the patient will develop aphasia, behavioral disturbance, cognitive impairment, and amnesia, as well as anxiety, apathy, aggressive emotions and behaviors. Studies have found that the incidence of AD increases with age. In today's society, with the intensification of population aging, the incidence of AD is increasing year by year. AD patients have high treatment and nursing costs and low self-care ability. They require special care, which places a heavy burden on society and families.

At present, the clinical effects of disease treatment are not ideal. After the onset of the disease, the patient's quality of life is adversely affected. At present, the pathogenesis of AD mainly includes the cholinergic theory, the tau protein hypothesis, the neurovascular theory, the oxidative stress theory, and the β-amyloid plaque theory [12].

β-secretase initiates protein hydrolysis by cleaving APP to produce neurotoxic fibers and deposits insoluble Aβ plaques at synaptic sites leading to synaptic dysfunction [13], [14], [15]. In June 2021, aducanumab was approved by the FDA for the treatment of patients with Alzheimer's disease. As the first approved AD drug in nearly 20 years, it targets the Aβ conformation and removes amyloid from the brains of AD patients [16]. Medications currently used to treat only relieve symptoms and improve memory in patients with early-onset disease, but do not cure or prevent disease progression [17].

In the discovery and research of medications, natural products play a crucial role. [18], [19]. Panaxadiol (PD) is a natural dammarane-type, tetracyclic triterpene. In recent years, research on PD has increased, and these studies have shown that PD exhibits good activity in vivo and in vitro in anti-AD related cells and in animal models [20].

A unique feature of carbamates is their ability to increase the interaction between the molecule and the target enzyme or receptor and can also modulate the biological properties of the molecule and improve its stability and pharmacokinetics. The structure of carbamates possesses very good chemical stability, proteolytic stability and the potential to increase the ability of molecules to cross cell membranes. Therefore, carbamate structural fragments have become the first choice for peptide bond substitution [21], [22], [23]. These excellent properties of carbamates have been widely used in drug design to improve drug-like properties along with increased potency, target specificity, and longer duration of action. In addition, carbamate fragments are widely used in the development of drugs against AD, as shown in Fig. S1, the marketed drug cabalactam, as well as in many literature reports of the neuroprotective effects of carbamate structure products M15 as an active fragment [24].

According to previous studies, structural modification of the carbamate fragment at the 3-OH position of PD showed a strong neuroprotective effect with an EC50 of 13.17 μM [25]. It has been reported that the introduction of piperazine, morpholine, and diethylamine fragments into the structure of natural products can significantly enhance their biological activity[26]. Therefore, piperazine carbamate derivatives Q3–Q8 were designed and synthesized, and piperazine bioelectronic equivalents Q1–Q2, Q9–Q12 were also synthesized. Compounds containing 1,2,3-triazoles are rich in biological activities, with anticonvulsant [27], [28], [29], [30], [31], [32], antibacterial [33], [34], anti-inflammatory [35], antitumor [36], anti-toxoplasma [37], [38], and anti-AD effects [39]. Therefore, the triazole carbamate Q24 was synthesized. The amino acid fragment has anti-AD activity [40]and enhances biological activity in the structural modification of natural products [41], [42]. Therefore, the amino acid carbamates Q25–Q29 were synthesized. Using molecular hybridization principles, a new series of carbamate derivatives of PD was designed and synthesized.