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  3. Design, synthesis, and evaluation of 1,4-benzodioxane-hydrazone derivatives as potential therapeutics for skin cancer: In silico, in vitro, and in vivo studies

Design, synthesis, and evaluation of 1,4-benzodioxane-hydrazone derivatives as potential therapeutics for skin cancer: In silico, in vitro, and in vivo studies

  • Bioorg Chem. 2025 Jun 15:160:108449. doi: 10.1016/j.bioorg.2025.108449.
Saleem Akbar 1,  Tushar Setia 1,  Subham Das 2,  Shalini Kumari 3,  Sk Batin Rahaman 4,  Mohd Wasim 4,  Bahar Ahmed 5,  Rikeshwer Prasad Dewangan 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard (Deemed to be University), New Delhi 110062, India.
  • 2 Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
  • 3 CSIR-Institute of Genomics and Integrative Biology (IGIB), Sukhdev Vihar, Mathura Road, New Delhi 110025, India.
  • 4 Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard (Deemed to be University), New Delhi 110062, India.
  • 5 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard (Deemed to be University), New Delhi 110062, India. Electronic address: baharjh59@gmail.com.
  • 6 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard (Deemed to be University), New Delhi 110062, India. Electronic address: rpdewangan@jamiahamdard.ac.in.
PMID: 40220711 DOI: 10.1016/j.bioorg.2025.108449
Abstract

In the pursuit of novel chemotherapeutic agents for skin Cancer, we synthesized a series of 1,4-benzodioxane-hydrazone derivatives (7a-l) using the Wolff-Kishner reaction. These compounds were initially screened against the NCI-60 oncological cell lines in a one-dose assay at 10 μM. Among them, compound 7e emerged as a potent inhibitor of Cancer cell growth across 56 cell lines, with an average GI50 of 6.92 μM. Notably, it exhibited enhanced efficacy in melanoma cell lines, including MDA-MB-435, M14, SK-MEL-2, and UACC-62, with GI50 values of 0.20, 0.46, 0.57, and 0.27 μM, respectively. Apoptosis assay and cell cycle analysis studies revealed that compound 7e induced Apoptosis and caused S-phase arrest in MDA-MB-435 cells. Furthermore, an in vitro enzyme inhibition assay against mTOR kinase yielded an IC50 of 5.47 μM, while molecular docking studies of compound 7e (docking score: -8.105 kcal/mol) supported its binding affinity. Compound 7e adhered to Lipinski's rule of five and displayed favourable ADMET properties. In vivo studies demonstrated its safety and efficacy in ameliorating skin Cancer in a mice model when administered intraperitoneally at 20 mg/kg. Structure-activity relationships were established through in vitro, in vivo, molecular docking, and molecular dynamics analysis. Collectively, these findings highlight 1,4-benzodioxane-hydrazone derivatives as promising scaffold for the development of novel chemotherapeutic agents for skin Cancer.

Keywords

1,4-Benzodioxane; Anticancer; Apoptosis; Cell cycle analysis; Molecular docking studies; Molecular dynamics; mTOR inhibitors.

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