Alzheimer's disease (AD), one of the most challenging neurodegenerative disorders, with high prevalence worldwide, is characterized by progressive cognitive decline and accumulation of amyloid-β plaques and neurofibrillary tau tangles. Despite significant research, the limited efficacy of current treatments underscores the critical need to identify novel pathogenic mechanisms and therapeutic targets. Necroptosis, a regulated and highly inflammatory form of programmed cell death, has emerged as one of the key contributors to AD pathogenesis. This systematic review comprises 25 high-quality in vivo, in vitro, and autopsy studies, published between 2015 and 2025, extracted from PubMed, Scopus, and Science Direct databases. The keywords include "necroptosis", "RIPK1", "RIPK3", "MLKL", "pMLKL", "necroptosis inhibitors", "Alzheimer’s disease", and "neurodegeneration". The review summarizes the multiple molecular mechanisms, including TNF-α/TNFR1 signaling, TRIF-mediated RIPK3 activation, and RHIM-dependent MLKL phosphorylation, associated with necroptosis in the pathogenesis of AD. All the studies converge on necroptosis as a central pathogenic pathway linking key molecular and cellular abnormalities observed in AD. The accumulated evidence strongly supports prioritizing the development of brain-penetrant necroptosis inhibitors and clinical validation of associated biomarkers. These insights signal a significant shift in AD therapeutics, moving from symptomatic treatment to mechanistically targeted interventions that can alter disease progression.

Backgrounds: This study explores the design of substituted tetrahydroquinoline (THQ) derivatives and their synthesis as possible inhibitors of mTOR inhibitors for targeted cancer therapy. Methods: Inspired by the structural characteristics of known mTOR inhibitors, eight novel derivatives were synthesized, characterized using mass spectroscopy, ¹H, and ¹³C NMR, and evaluated for anticancer activity. Results: Computational studies, including molecular docking and molecular dynamics (MD) simulations, highlighted the derivative’s strong binding interaction and stability within the mTOR active site. Assays for in vitro cytotoxicity showed strong and specific anticancer action against cell lines of triple-negative breast cancer, lung cancer, and breast cancer while causing negligible impact on healthy cells. Conclusions: Compound 10e emerged as the most promising candidate, displaying exceptional activity against A549 cells (IC₅₀ = 0.033 µM) and inducing apoptosis in a dose-dependent manner, surpassing standard agents, like Everolimus and 5-flurouracil. Structure–activity relationship analysis revealed that incorporating trifluoromethyl and morpholine moieties significantly enhanced selectivity and potency. MD simulations further validated these findings, confirming stable protein-ligand interactions and favorable dynamics over a 100-ns simulation period. Collectively, this study underscores the therapeutic potential of THQ derivatives, particularly compound 10e, as promising mTOR inhibitors with potential applications in lung cancer treatment.