Exploring Tetrahydroquinoline Derivatives: A New Frontier in Cancer Treatment

Suman K. Shaw; Rajdeep Dey; Ruchi Yadav; Aliasgar Baldiwala; Manan Patel; Bhumika D. Patel; Hardik G. Bhatt; Gopal Natesan; Abhishek Jha; Udit Chaube

doi:10.1055/a-2595-8088

Synlett, Table of Contents

Synlett 2025; 36(16): 2577-2584
DOI: 10.1055/a-2595-8088

letter

Small Molecules in Medicinal Chemistry

Exploring Tetrahydroquinoline Derivatives: A New Frontier in Cancer Treatment

Authors

Suman K. Shaw‡

^aDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
Rajdeep Dey‡

^aDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
Ruchi Yadav

^aDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
Aliasgar Baldiwala

^bInstitute of Pharmacy, Nirma University, Ahmedabad 382481, India
Manan Patel

^bInstitute of Pharmacy, Nirma University, Ahmedabad 382481, India
Bhumika D. Patel

^aDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
Hardik G. Bhatt

^aDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
Gopal Natesan

^aDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
Abhishek Jha

^cDepartment of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Udit Chaube ∗

^aDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India

Abstract

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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

Full Text

References

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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.

Supplementary Material

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