Design, synthesis, and mechanistic insights into the anti-proliferative activity of Novel N9-substituted harmine derivatives

Kancherla, Rajesh and K, Ravi Singh and G.R. Satyanarayana and M.B. Madhusudana Reddy, Vinay Kumar D Cand Lohith T Nand Ashok Reddy Katla (2026) Design, synthesis, and mechanistic insights into the anti-proliferative activity of Novel N9-substituted harmine derivatives. Journal of Molecular Structure, 1355. p. 144922. ISSN 1872-8014

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Official URL: https://doi.org/10.1016/j.molstruc.2025.144922

Abstract

To explore the therapeutic promise of harmine chemistry, the two novel derivatives 3a and 3b were synthesized through N-alkylation of plant-derived harmine using sodium hydride and the corresponding halide precursors (2a and 2b) in dimethylformamide at room temperature. Structural characterization was performed using ¹H NMR, ¹³C NMR, and HRMS analyses. Density Functional Theory (DFT) calculations were employed to investigate the stability and molecular properties of the synthesized derivatives. Further, the compounds were tested for anti-proliferative activity against breast cancer cell lines (MCF-7 and MDA-MB-231) and for cytotoxicity against the Human Embryonic Kidney derived HEK-293T cell line. Their ability to suppress the expression of proliferation-associated genes (ER, Ki67 and AGR2) was examined, supported by molecular docking studies against key oncogenic targets (CAD, mPGES-1, and CTLA-4). Compound 3a exhibited stronger growth-inhibitory effects (IC₅₀: 27.94 ± 0.96 µM) compared to 3b, with lower toxicity toward normal cells. ADMET predictions suggested good oral bioavailability and minimal mutagenic or carcinogenic risk. These results indicate that N9-substituted harmine derivatives hold promise for further development as anti-breast cancer agents.

Item Type: Article
Uncontrolled Keywords: Harmine Derivatives, DFT calculations, Breast Cancer activity, qRT PCR Gene Expression, Molecular Docking, ADME Studies
Subjects: C Chemical Science > Chemistry
Divisions: Department of > Chemistry
Depositing User: C Swapna Library Assistant
Date Deposited: 26 Dec 2025 10:39
Last Modified: 26 Dec 2025 10:39
URI: http://eprints.uni-mysore.ac.in/id/eprint/18239

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