Synthesis of new functionalized bioactive S-substituted indolyl-triazoles as cytotoxic and apoptotic agents through multi-targeted kinase inhibition

Ahmed T A Boraei; Mohamed S Nafie; Assem Barakat; Tomohiro Tanaka; Koshu Kawano; Toshifumi Tojo; Shin Aoki; Ahmed A M Sarhan

doi:10.1016/j.bioorg.2025.108154

Synthesis of new functionalized bioactive S-substituted indolyl-triazoles as cytotoxic and apoptotic agents through multi-targeted kinase inhibition

Bioorg Chem. 2025 Jan 10:156:108154. doi: 10.1016/j.bioorg.2025.108154. Online ahead of print.

Authors

Ahmed T A Boraei¹, Mohamed S Nafie², Assem Barakat³, Tomohiro Tanaka⁴, Koshu Kawano⁵, Toshifumi Tojo⁶, Shin Aoki⁷, Ahmed A M Sarhan⁸

Affiliations

¹ Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt. Electronic address: [email protected].
² Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt; Department of Chemistry, College of Sciences, University of Sharjah, Sharjah (P.O. Box 27272), United Arab Emirates.
³ Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. Electronic address: [email protected].
⁴ Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan; Faculty of Pharmaceutical Sciences, Tokyo University of Science 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
⁵ Faculty of Pharmaceutical Sciences, Tokyo University of Science 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
⁶ Faculty of Pharmaceutical Sciences, Tokyo University of Science 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Research Institute for Science and Technology (RIST), Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
⁷ Faculty of Pharmaceutical Sciences, Tokyo University of Science 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Research Institute for Science and Technology (RIST), Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Research Institute for Biomedical Science (RIBS), Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
⁸ Chemistry Department, Faculty of Science, Arish University, Al-Arish 45511, Egypt.

PMID: 39827652
DOI: 10.1016/j.bioorg.2025.108154

Abstract

The search for new anticancer compounds is a major focus for researchers in chemistry, biology, and medicine. Cancer affects people of all ages and regions, with rising incidence rates. It does not discriminate by age or gender, making it a significant threat to humanity. Therefore, discovering new treatments is essential. As a result, new 3-S-alkylated 4-amino-5-indolyl-triazoles 2a-e were synthesized by the alkylation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with the appropriate alkylating agent using K₂CO₃ in EtOH/DMF. Hydrazinolysis of ester 2a afforded the hydrazide 3 which was converted into the substituted thiosemicarbazide 4 by reaction with 4-chlorophenyl isothiocyanate. The substituted thiosemicarbazide 4 was cyclized to triazole-3-thione 5 by reflux in 4.0 N aqueous KOH. The hit compound 6 obtained from triazole-3-thione 5 by alkylation with ethyl chloroacetate. For cytotoxicity, interestingly, compound 6 was exhibited potent cytotoxicity with IC₅₀ values of 11 and 8.5 μM compared to Erlotinib (IC₅₀ = 3.5 μM). At the same time, other compounds exhibited poor cytotoxicity with higher IC₅₀ values. Compound 6 was investigated regarding the apoptosis activity in A549 and Jurkat cells. It induced total apoptosis in A549 cells by 38-fold, and it induced total apoptosis in Jurkat cells by 15.9-fold, arresting the cell cycle in both cell lines at the S-phase. Additionally, compound 6 exhibited potent EGFR/AKT/ERK/P38-MAPKα inhibition in both enzyme targeting and molecular docking studies. Accordingly, compound 6 can be further developed as kinase-targeted anti-lung cancer.

Keywords: Alkylation; EGFR/AKT/ERK/P38-MAPKα inhibition; Indolyl-triazoles; Lung carcinoma; T cell leukemia.