To find new molecules that would retain structural stability and excellent therapeutic properties, great attention is paid to stilbenes and their derivatives, known for their excellent therapeutic effects [1]. Most stilbene structures found in nature have excellent therapeutic properties thanks to their antioxidant activity [2], [3], [4]. Stilbenes are found in various natural compounds but most often in plants that synthesize them to protect themselves from adverse environmental conditions. The primary role of stilbene in plants is to protect cells from oxidative stress, and some of them also act as toxins against various pathogens [5].

Particularly interesting in this sense are their hydroxyl derivatives emphasizing the compound resveratrol (Fig. 1) [6]. Trans-resveratrol (Fig. 1) is a molecule that belongs to stilbenes and is the most famous hydroxy-derivative from this group of compounds. It is known to act as an antioxidant, and according to the latest research, trans-resveratrol actively participates in several mechanisms in the pathology of Alzheimer's disease (AD) [7], [8]. In the human body, trans-resveratrol is biosynthesized by the enzyme stilbene synthase [9], [10], and it was found that it destroys and inhibits the formation of preformed aggregates, reduces the activation of microglia and the Sirtuin1 (Sirt1) biological pathway, which modulates the transmission of nerve signals in the body [11]. Despite the proven positive effects, further research is needed to prove the safety and functionality of trans-resveratrol in the human body. Due to the presence of the ethylene fragment within its structure, hydroxy-stilbenes exist as isomeric structures; that is, cis- and trans-configurations of each molecule are possible. When investigating isomeric forms of hydroxy-stilbenes and their biological potential, it should be kept in mind that trans-isomers are more often present in natural compounds and are more stable and biologically active than cis-isomers [5]. Most currently known biological active hydroxylated stilbene structures belong to trans-resveratrol analogs (Fig. 1).

Numerous studies have shown that stilbene, and especially resveratrol and its analogs, have a similar effect on human health and show pronounced antioxidant, antitumor, antimicrobial, anti-inflammatory, anti-neurodegenerative, antiviral, and antidiabetic properties [12]. In addition to the properties mentioned above, it has been shown that stilbenes and analogs act as luminophores due to the possibility of interaction with radiation [13], [14].

Antioxidants are generally considered substances whose properties make it possible to slow down or even prevent the oxidation of biological substrates caused by reactive substances such as free radicals [15]. As a result of increasingly stressful living conditions in the human body, more and more free radicals are formed, which then damage proteins, DNA, and lipids, leading to various diseases [16]. Mechanistically, the antioxidant activity is based on the antioxidant's ability to trap free radicals in the molecular skeleton and release hydrogen atoms. If favorable functional groups and positions in the structure are chosen, the antioxidant activity can be increased with the appearance of new effects, such as improved diffusion through the cell membrane and bioavailability. Trans-resveratrol is proven as an agent that reduces changes in mitochondrial potential, thus inhibiting the accumulation of free radicals [17]. Because of this fact, hydroxy-stilbenes are recognized as a building block of great potential due to various possible structural modifications and the application of their therapeutic properties in medicine [5], [18].

Hydroxy-stilbenes are also potentially used in treating Alzheimer's and Parkinson's diseases thanks to the possibility of synthesizing their small amphiphilic derivatives. The permeability of the blood–brain barrier (BBB) for amphiphilic derivatives exceeds the results for biological molecules investigated so far precisely because of the differences in the hydrophobic and hydrophilic parts of the molecules, which further increase the binding affinity of hydroxy-stilbene to Aβ (β-amyloid) oligomers, which are one of the causes of continuous synaptic damage [19]. It has been proven that the natural polyphenol trans-resveratrol benefits the nervous system [20], [21], [22]. Resveratrol and its derivative pterostilbene (Fig. 1) protect against dementia syndromes such as AD, as research on mammalian cells determined. Resveratrol has shown great potential in neurological protection, in vitro and in vivo research. It has been found to facilitate the breakdown of amyloid precursor protein and aid in removing neurotoxic amyloid-β peptides. It reduces damage to nerve cells by activating NAD+-dependent histone deacetylases known as sirtuins [23]. By increasing the resolution of β-amyloid and modulating intracellular effectors related to oxidative stress, neuronal energy homeostasis, apoptosis, and cell longevity, trans-resveratrol has an anti-neurodegenerative effect [24]. Testing on mice proved that trans-resveratrol protects neurons from polyglutamine (polyQ) toxicity in Huntington's disease and also from Wallerian degenerative decline in research [7]. Also, it acts as a neuroprotector in PC12 cells, protects against Aβ25-35 induced toxicity, and weakens cell apoptosis [17].

Furthermore, trans-resveratrol is safe and well tolerated in patients with mild to moderate AD [25], [26]. Since AD is characterized by low levels of acetylcholine in the patient's brain, current pharmacology is based on drugs that inhibit cholinesterases to enhance cholinergic neurotransmission. Oxidative stress is also an important aspect that must be considered in neurodegenerative disease research. It can be concluded that hydroxy-stilbenes (especially trans-resveratrol) are very interesting in terms of multiple uses in therapeutic applications thanks to their biological action.

In our laboratory, in previous scientific research, thiophene analogs of hydroxy-stilbene, derivatives 1 and 2 (Fig. 2), showed good biological activity [27], with potential inhibition of cholinesterase enzymes and high values for antioxidant activity due to the presence of the heteroaromatic ring. Applying rational design principles, we strategically incorporated the thiophene ring into the resveratrol scaffold and explored different combinations of substituents and their positions to enhance the biological activity of novel compounds. Compounds 1 and 2 were used as a starting point for developing new resveratrol analogs in this research. New compounds will be analyzed for their inhibitory effects on cholinesterase and antioxidant properties, making them an interesting new group of structures for further profiling as active components.