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

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 KCO 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 IC values of 11 and 8.5 μM compared to Erlotinib (IC = 3.5 μM). At the same time, other compounds exhibited poor cytotoxicity with higher IC 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.