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Alzheimer's disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease's progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In this review, we cover hybrid molecules published between 2014 and 2024. We offer an overview of the strategies employed in drug design and approaches that have led to notable improvements and reduced hepatotoxicity. Our aim is to offer insights into the potential development of new Alzheimer's disease drugs. This overview highlights the potential of multi-target drugs featuring heterocycles with N-benzylpiperidine fragments and natural compounds in improving Alzheimer's disease treatment. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease is characterized by progressive, irreversible degeneration of acetylcholine‐producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The natural decline in melatonin levels with aging has been associated with insomnia and depression as well as the development of neurodegenerative disorders such as AD. Furthermore, the complexity of AD pathology has encouraged the design of molecules that are able to interact with two or more complementary targets, with the expectation that these multitarget ligands (MTL) may represent important advantages in the treatment of the disease. This study aimed to find new ChE inhibitors with improved toxicity. Method: In vitro toxicity screening of the newly compounds on human neuroblastoma SH‐SY5Y, mouse neuroblastoma cell line Neuro‐2a and mouse fibroblast cells CCL‐1. The viability of the cells was assessed by MTT assay. The neuroprotective properties of the compounds were determined in a model of H2O2‐induced oxidative damage in SH‐SY5Y cells. For comparison, effects donepezil, melatonin and galanthamine were determined. Result: Most of the compounds have IC50 values over 100 µM. Compound 3f possess statistically significant protective effects. It should be noted that the neuroprotective effects were more pronounced than those of donepezil and similar to melatonin and rasagiline. Conclusion: The new series of melatonin derivatives with donepezil fragment exhibit low toxicity and a good in vitro safety profile. Further, in vitro protection study proved efficient prevention against oxidative stress in H2O2‐induced injury in SH‐SY5Ycells, especially by compound 3f and was proven as the most perspective for further investigations. Acknowledgments: The financial support by the National Science Fund of Bulgaria (Grant KP‐06‐Н63/11 14.12.2022) is gratefully acknowledged. [ABSTRACT FROM AUTHOR]