Alzheimer’s disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone (3a–r) or sulfonyl hydrazone (5a–l) fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds (3c and 3d) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system. Compound 3n, possessing two indole scaffolds, showed the highest activity against butyrylcholinesterase (BChE) and a high selectivity index (SI = 47.34), as well as a pronounced protective effect in H₂O₂-induced oxidative stress in SH-SY5Y cells. Moreover, compounds 3c, 3d, and 3n showed low neurotoxicity against malignant neuroblastoma cell lines of human (SH-SY5Y) and murine (Neuro-2a) origin, as well as normal murine fibroblast cells (CCL-1) that indicate the in vitro biocompatibility of the experimental compounds. Furthermore, compounds 3c, 3d, and 3n were capable of penetrating the blood–brain barrier (BBB) in the experimental PAMPA-BBB study. The molecular docking showed that compound 3c could act as a ligand to both MT1 and MT2 receptors, as well as to AchE and BchE enzymes. Taken together, those results outline compounds 3c, 3d, and 3n as promising prototypes in the search of innovative compounds for the treatment of AD-associated neurodegeneration with oxidative stress. This study demonstrates that hydrazone derivatives with melatonin and donepezil are appropriate for further development of new AChE/BChE inhibitory agents.

Acetylcholinesterase (AChE) is one of the classical targets in the treatment of Alzheimer’s disease (AD). Inhibition of AChE slows down the hydrolysis of acetycholine and increases choline levels, improving the cognitive function. The achieved success of plant-based natural drugs acting as AChE inhibitors, such as galantamine (GAL) from Galanthus genus and huperzine A from Huperzia serrate (approved drug in China), in the treatment of AD, and the fact that natural compounds (NCs) are considered as safer and less toxic compared to synthetic drugs, led us to screen the available NCs (almost 150,000) in the ZINC12 database for AChE inhibitory activity. The compounds were screened virtually by molecular docking, filtered for suitable ADME properties, and 32 ligands from 23 structural groups were selected. The stability of the complexes was estimated via 1 μs molecular dynamics simulation. Ten compounds formed stable complexes with the enzyme and had a vendor and a reasonable price per mg. They were tested for AChE inhibitory and antioxidant activity. Five compounds showed weak AChE inhibition and three of them exhibited high antioxidant activity.

Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more effective AChE inhibitors continues. We generated a fragment-based library containing aromatic moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic fragment (Ar). The newly designed compounds were screened virtually for blood–brain barrier (BBB) permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and could serve as a lead molecule for further optimization and development.

The genus Galanthus (Amaryllidaceae) currently contains 25 plant species naturally occurring in Europe and the Middle East region. These perennial bulbous plants possess well-known medicinal and ornamental qualities. Alkaloid diversity is their most distinctive phytochemical feature. A total of 127 compounds (≈20% of all known Amaryllidaceae alkaloids) grouped in 16 structural types have been previously found in Galanthus extracts. Some structural types like galanthindole, graciline and plicamine were first discovered in Galanthus plants. Nine Galanthus species, however, remain unstudied regarding their alkaloid patterns. Intraspecific variability has only been studied in G. nivalis and G. elwesii. Amaryllidaceae alkaloids are molecules with anticholinesterase, antibacterial, antifungal, antiviral and anticancer properties. Galanthamine, isolated for the first time from Galanthus woronowii Losinsk., stands out as an acetylcholinesterase inhibitor approved for medical use by the FDA for the treatment of symptoms of Alzheimer’s disease. Lycorine, narciclasine and pancratistatin are noteworthy cytotoxic and antitumor alkaloids. Structural types like galanthamine, homolycorine and haemanthamine are fairly well studied in anticancer research, but little to no information is available on galanthindole, graciline and other types. This review aims to present an update on the alkaloid diversity of Galanthus spp. and highlight the need for further research on the antitumor potential of these molecules.

The application of natural products for pest control is important in modern farming. In the present study, Artemisia santonicum L. and Artemisia lerchiana Weber essential oil and exudate profiles were determined, and their potential as inhibitors of seed germination, acetylcholinesterase, and phytopathogenic mycelium growth were evaluated. Essential oils (EO) were obtained via hydrodistillation and exudates (AE) by washing aerial parts of the species with acetone. EO and AE’s composition was identified using GC/MS. Eucalyptol (1,8-cineole) and camphor were found to be the main components of A. lerchiana EO, while β-pinene, trans-pinocarveol, α-pinene, α-terpineol, and spathulenol were established as major compounds of A. santonicum EO. Strong inhibition on Lolium perenne seed germination was found at 2 µL/mL and 5 mg/mL using aqueous solutions of EO and AE, respectively. An inhibitory effect on acetylcholinesterase was established, with an IC₅₀ value of 64.42 and 14.60 μg/mL for EO and 0.961, >1 mg/mL for the AE of A. lerchiana and A. santonicum, respectively. The low inhibition on the mycelium growth of studied phytopathogenic fungi was established by applying 2 µL of EO and 15 µL of 100 mg/mL of AE, with the exception of A. lerchiana AE against Botrytis cinerea. These results show that the studied EO and AE exhibited strong phytotoxic and AChE inhibitory activities, providing new data for these species.

In recent years, the essential oil of Satureja species has been studied as a source of biocidal activity with potential applications in organic farming such as bio-pesticides. The present study aims to determine the potential of essential oil (EO), exudate fraction (EF) and methanolic extract (ME) of Satureja kitaibelii Wierzb. ex Heuff. to inhibit the mycelial growth of phytopathogenic fungi and acetylcholinesterase (AChE). Additionally, ME was tested for inhibitory activity on seed germination and root elongation. Phytochemical analysis was conducted using gas chromatography–mass spectrometry (GC–MS) and thin-layer chromatography (TLC). Biological activities were studied using in vitro methods. p-Cymene, limonene, geraniol, carvacrol and borneol were identified as the main components of EO. Oleanolic and ursolic acid, carvacrol and flavonoid aglycones were determined as the most abundant bioactive compounds of EF, whereas rosmarinic acid and flavonoid glycosides were found in ME. EO reduced the growth of all tested plant pathogens, indicated by 40% to 84% inhibition of mycelial growth (IMG). The growth rates of oomycetes Phytophthora cryptogea Pethybr. & Laff. and Phytophthora nicotianae Breda de Haan were affected to the greatest extent with 84% and 68% IMG. EF showed the most potent AChE inhibitory activity with IC₅₀ value of 0.18 mg/mL. Aqueous solutions of the ME with a concentration above 5 mg/mL were found to inhibit seed germination by more than 90%, whereas a reduction in root elongation was observed at 3 mg/mL. The present study provides for the first time data for the pesticidal properties of EO, EF and ME of S. kitaibelii.