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

Rajesh, K. and Singh, Ravi K. and Vinay Kumar, D. C. and Lohith, T. N. and Reddy, Ashok K. and Satyanarayana, G. R. and Reddy, Madhusudana M. B. (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: 16 Jul 2026 05:46
URI: http://eprints.uni-mysore.ac.in/id/eprint/18239

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