Design and Microwave-Assisted Synthesis of Aza-Resveratrol Analogs with Potent Cholinesterase Inhibition

Background: Currently approved Alzheimer’s disease medications mainly comprise acetylcholinesterase inhibitors. Many of these inhibitors are either natural compounds or synthetic molecules inspired in natural compounds. Hybrid molecules that can interact with different target sites of the enzyme could lead to the discovery of effective multitarget drugs. Objective: To design, synthesize, and evaluate a series of new aza-resveratrol analogs as in vitro acetyl- and butyrylcholinesterase inhibitors. Methods: The synthesis is achieved by a simple and efficient microwave-assisted method, from commercially available starting materials. Compounds are designed as hybrids of an aza-stilbene nucleus (Schiff base) connected to a tertiary amine by a hydrocarbon chain of variable length, designed to interact both with the peripheric anionic site and the catalytic site of the enzyme. Results: All the derivatives inhibit both enzymes in a concentration-dependent manner, acting as moderate to potent cholinesterase inhibitors. The most potent inhibitors are compounds 12b (IC50 = 0.43 μM) and 12a (IC50 = 0.31 μM) for acetyl- and butyrylcholinesterase, respectively. Compounds 12a and 12b also exhibit significant acetylcholinesterase inhibition in SH-SY5Y human neuroblastoma cells without cytotoxic properties. Enzyme kinetic studies and molecular modeling reveal that inhibitor 12b targets both the catalytic active site and the peripheral anionic site of acetylcholinesterase what makes it able to modulate the self-induced β-amyloid aggregation. Furthermore, the molecular modeling analysis helps to assess the impact of the linker length in the inhibitory activity of this family of new cholinesterase inhibitors. Conclusion: These compounds have the potential to serve as a dual binding site inhibitor and might provide a useful template for the development of new anti-Alzheimer’s disease agents.

Resveratrol and other Stilbenes: Effects on Dysregulated Gene Expression in Cancers and Novel Delivery Systems

: Trans-resveratrol (RESV), pterostilbene, trans-piceid and trans-viniferins are bioactive stilbenes present in grapes and other plants. Several groups applied biotechnology to introduce their synthesis in plant crops. Biochemical interaction with enzymes, regulation of non-coding RNAs, and activation of signaling pathways and transcription factors are among the main effects described in literature. However, solubility in ethanol, short half-life, metabolism by gut bacteria, make difficult to achieve the concentration responsible for the effects observed in cultured cells. Derivatives obtained by synthesis, trans-resveratrol analogs and methoxylated stilbenes show to be more stable and allow the synthesis of bioactive compounds with higher bioavailability. However, changes in chemical structure may require testing for toxicity. Thus, delivery of RESV and its natural analogs incorporated into liposomes or nanoparticles, is the best choice to ensure stability during administration and appropriate absorption. The application of -RESV and its derivatives with anti-inflammatory and anticancer activity is presented with description of novel clinical trials.

Aza- and Azo-Stilbenes: Bio-Isosteric Analogs of Resveratrol

Several series of natural polyphenols are described for their biological and therapeutic potential. Natural stilbenoid polyphenols, such as trans-resveratrol, pterostilbene and piceatannol are well-known for their numerous biological activities. However, their moderate bio-availabilities, especially for trans-resveratrol, prompted numerous research groups to investigate innovative and relevant synthetic resveratrol derivatives. This review is focused on isosteric resveratrol analogs aza-stilbenes and azo-stilbenes in which the C=C bond between both aromatic rings was replaced with C=N or N=N bonds, respectively. In each series, synthetic ways will be displayed, and structural sights will be highlighted and compared with those of resveratrol. The biological activities of some of these molecules will be presented as well as their potential therapeutic applications. In some cases, structure-activity relationships will be discussed.