ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Exploring phenothiazine derivatives: green synthesis, computational modelling, and experimental validation for breast cancer therapy

C. S. Sreelekshmi, Shiny P. Laila, B. Arunkumar, V. S. Vishnu, K. S. Sandhya, Praveen Kumar, Pooja P. Rajan, P. R. Kavitha Rani, and Annette Fernandez

Department of Chemistry, University College, Thiruvananthapuram, India

E-mail: shinylaila2014@universitycollege.ac.in

Received: 23 June 2025  Accepted: 21 November 2025

Abstract:

Hydroxynaphthoquinones are a class of naphthoquinone derivatives containing one or more hydroxyl groups which parade diverse bioactivities, including anticancer effects. Taking into consideration of this aspect, three novel heterocyclic phenothiazine derivatives of the naturally occurring hydroxynaphthoquinones namely Plumbagin (1a), Juglone (1b) and Lawsone (1c) were synthesized using ultrasound irradiation method, a green chemistry method. The derivatives 1-Hydroxy-6-methyl-5H-benzo[a]phenothiazin-5-one (2a), 1-Hydroxy-5H-benzo[a]phenothiazin-5-one (2b) and 6-((2-Mercaptophenyl)amino)-5H-benzo[a]phenothiazin-5-one (2c) were characterized using various spectral techniques and single crystal studies. The present study also focuses on a comprehensive comparison of in silico study with estrogen receptor protein (Estradiol) with in vitro pharmacological studies in MCF-7 cell lines. Molecular docking studies in Estradiol protein proved that the compounds showed a good inhibition towards the aforesaid protein that induces cancer. The nature of activity of compounds in normal cell lines were tested to ascertain the toxicity of the said compounds. In silico molecular docking and molecular dynamic simulation techniques were also conducted to identify superior candidates for further investigation. In vitro results from breast cancer cell lines, revealed that from among the derivatives, 2b possess the highest activity in MCF-7, with lower LC₅₀ value of 16.59 µg/mL and is comparable with LC₅₀ of standard drug Doxorubicin. All derivatives were further explored for in vitro cytotoxicity testing in normal L929 cell lines (fibroblast). 2b had a lower toxicity compared to that of Doxorubicin. The compounds were subjected to antimicrobial activity against Staphylococcus aureus and Klebsiella pneumoniae indicated that 2b exhibited better activity against both. Thus, the compound 2b may serve as a lead molecule in future investigations related to drug discovery.

Keywords: Breast cancer; Plumbagin; Juglone; Lawsone; MCF-7; L929; GROMACS; CHARMM

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-025-04543-1

Chemical Papers 80 (3) 2681–2699 (2026)