Journal Article Epublish 3 citations
PubMed: 40661216 DOI: 10.1039/d5ra02512e
Synthesis and multi-target antiproliferative evaluation of novel 1,2,4-triazole-3-thione analogues against breast cancer: in silico and in vitro mechanistic insights.
RSC Adv 15(30):24769-24790
Authors: Hussain Ali Almasmoum, Ghassan Almaimani, Riyad A Almaimani, Abdullatif Taha Babakr, Maha Alsunbul, Hussah Abdullah Alshwyeh, Eman Serry Zayed, Ibrahim Abdel Aziz Ibrahim, Essa M Saied
Affiliations
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University Makkah Kingdom of Saudi Arabia.
- Department of Surgery, Faculty of Medicine, Umm Al-Qura University Al Abdeyah, P. O. Box 7607 Makkah Saudi Arabia.
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University Al Abdeyah Makkah 24381 Saudi Arabia.
- Department of Pharmaceutical Sciences. College of Pharmacy, Princess Nourah Bint Abdulrahman University P. O. Box 84428 Riyadh 11671 Saudi Arabia.
- Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University 31441 Dammam Saudi Arabia. Basic & Applied Scientific Research Centre, Imam Abdulrahman Bin Faisal University P. O. Box 1982 31441 Dammam Saudi Arabia.
- Department of Clinical Biochemistry, Faculty of Medicine, University of Tabuk Tabuk Saudi Arabia.
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University Makkah Saudi Arabia.
- Chemistry Department, Faculty of Science, Suez Canal University Ismailia 41522 Egypt.
- Institute for Chemistry, Humboldt Universität zu Berlin 12489 Berlin Germany.
Abstract
Cancer remains a major global health challenge, with breast cancer representing the most commonly diagnosed malignancy in women. Heterocyclic scaffolds containing nitrogen and sulfur, such as 1,2,4-triazole-3-thione derivatives, have shown broad pharmacological utility, including notable anticancer potential. In the present study, a novel series of 4,5-disubstituted-1,2,4-triazol-3-thione derivatives was designed, synthesized, and fully characterized using NMR, IR, MS, and elemental analysis. The compounds were evaluated for their antiproliferative effects against MCF-7 (breast cancer) and HepG2 (liver cancer) cell lines. Most derivatives demonstrated notable cytotoxicity, with compound 6 exhibiting the most potent activity, achieving IC 50 values of 4.23 μM and 16.46 μM against MCF-7 and HepG2 cells, respectively, comparable to the reference drug vinblastine. Mechanistic investigations revealed that compound 6 acts via a multi-targeted pathway, significantly inhibiting α-glucosidase (IC 50 = 122.7 μM), tubulin-β polymerization (58.5% inhibition), and aromatase activity (31% reduction). Flow cytometry analysis confirmed that compound 6 induces pronounced S-phase cell cycle arrest and promotes both early and late apoptotic cell populations, along with a moderate increase in necrosis in MCF-7 cells. Additionally, compound 6 displayed dose-dependent antioxidant activity (DPPH IC 50 = 25.4 μM), comparable to trolox. Complementary in silico studies provided molecular-level insights into the interactions of compound 6 with its biological targets. Molecular docking showed strong binding affinities through key hydrogen bonding and hydrophobic interactions within the active sites of tubulin, α-glucosidase, and aromatase. Molecular dynamics simulations over 100 ns confirmed the stability of these interactions, especially with α-glucosidase, supported by consistent RMSD, compactness, and favorable per-residue energy contributions. Overall, these findings identify compound 6 as a promising multi-target lead for further development as an anticancer agent, combining cytotoxic, enzyme-inhibitory, and antioxidant properties.
MeSH
Cells, Thiones, Tubulin, Aromatase, Breast Neoplasms, Neoplasms, Multiple Chronic Conditions, Triazoles, Glucosidases, Antioxidants, Breast