Efforts have been made to find an efficient scaffold (and its substitution) that can be used for the treatment of lung cancer via mTOR inhibition. A detailed literature search was carried out for p... Graphical abstract

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.

This study explores the design and synthesis of substituted tetrahydroquinoline (THQ) derivatives as potential mTOR inhibitors for targeted cancer therapy. Inspired by the structural characteristics of known mTOR inhibitors, eight novel derivatives were synthesized, characterized using advanced spectroscopic techniques, and evaluated for anticancer activity. Computational studies, including molecular docking and molecular dynamics (MD) simulations, highlighted the derivative's strong binding affinity and stability within the mTOR active site. In-vitro cytotoxicity assays demonstrated potent and selective anticancer activity against A549, MCF-7, and MDA-MB-231 cancer cell lines, with minimal toxicity toward normal cells. 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.