Exploring Tetrahydroquinoline Derivatives: A New Frontier in Cancer Treatment

Abstract

Tetrahydroquinoline derivatives are emerging as promising anticancer agents due to their versatile biological activities. In this study, we designed, synthesized, and evaluated six novel tetrahydroquinoline derivatives with anticancer potential. The compounds were synthesized by nitration, benzoylation, and reduction, achieving high yields and structural diversity. Molecular-docking studies on the mTOR protein (PDB ID: 4JT6) revealed strong binding affinities, with key interactions at active-site residues. Molecular dynamics simulations in GROMACS (50 ns) confirmed the stability of the compound–protein complexes. In vitro cytotoxicity assays against A549, MDA-MB-231, and MCF-7 cancer cell lines showed potent activities, with one product displaying an IC₅₀ o

Key words

anticancer drugs - tetrahydroquinolines - molecular docking

Publication History

Received: 27 February 2025

Accepted after revision: 28 April 2025

Accepted Manuscript online:
28 April 2025

Article published online:
12 June 2025

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• 40 3,5-Difluoro-N-[1-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-7-yl]benzamide (13a); Typical Procedure Me₃NH (4.9 mmol, 0.46 mL) was added dropwise to a solution of compound 11a (1.7 mmol, 0.5 g) in CH₂Cl₂, and the mixture was stirred for 30 min at r.t. 3,5-Difluorobenzoyl chloride (1.6 mmol, 0.28 g) was added, and the resulting mixture was stirred for 1 h, then poured onto crushed ice. The mixture was extracted with CH₂Cl₂, and the extracts were dried (Na₂SO₄), concentrated, and purified by column chromatography to give a light-yellow solid; yield: 39.46%; mp 206–208 °C; HPLC purity: 99.45%. ¹H NMR (400 MHz, CDCl₃): δ = 1.68–1.65 (d, J = 12 Hz, 4 H, CH₂), 1.99–1.92 (m, 4 H, CH₂), 2.75–2.71 (t, J = 12 Hz, 2 H, CH₂), 3.28 (s, 1 H, CH), 3.44–3.27 (t, J = 12 Hz, 2 H, CH₂), 4.0–3.97 (d, J = 12 Hz, 2 H, CH₂), 7.045–7.00 (t, J = 8 Hz, 2 H, ArCH); 7.18–7.13 (d, J = 8 Hz, 1 H, ArCH), 7.48–7.41 (m, 1 H, ArCH), 7.83 (s, 1 H, ArCH), 7.86 (s, 1 H, NH–CO). ¹³C NMR (100 MHz, CDCl₃): δ = 24.16, 26.32, 29.43, 29.66, 31.40, 38.60, 42.98, 67.05, 112.0, 112.25, 114.21, 114.41, 114.61, 116.20, 128.87, 132.00, 132.11, 135.43, 139.33, 158.65, 161.1, 174.86. MS (EI): m/z [M + H]⁺ calcd for C₂₂H₂₃F₂N₂O₃: 400.43; found: 401.49.