Morpholine-Substituted Tetrahydroquinoline Derivatives as Potential mTOR Inhibitors: Synthesis, Computational Insights, and Cellular Analysis

<b>Backgrounds:</b> This study explores the design of substituted tetrahydroquinoline (THQ) derivatives and their synthesis as possible inhibitors of mTOR inhibitors for targeted cancer therapy. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> Compound <b>10e</b> 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 <b>10e</b>, as promising mTOR inhibitors with potential applications in lung cancer treatment.