LAUSR

Cancer is the most severe disease worldwide. Every year, tens of millions of people are diagnosed with cancer, and over half of those people will ultimately die from the disease. Hence, the discovery of new inhibitors for fighting cancer is necessary. As a result, new indolyl-triazole hybrids were synthesized to target breast and liver cancer cells. The synthetic strategy involves glycosylation of the 4-aryltriazolethiones 3a–b with acetyl-protected α-halosugars in the presence of K2CO3 in acetone to give a mixture of β-S-glycosides 6a–b, 7a–b, and β-N-glycosides 8a–b, 9a–b. Chemo-selective S-glycosylation was achieved using NaHCO3 in ethanol. The migration of glycosyl moiety from sulfur to nitrogen (S → N glycosylmigration) was achieved thermally without any catalyst. Alkylation of the triazole-thiones with 2-bromoethanol and 1-bromopropan-2-ol in the presence of K2CO3 yielded the corresponding S-alkylated products. The synthesized compounds were tested for their cytotoxicity using an MTT assay and for apoptosis induction targeting PARP-1 and EGFR. Compounds 12b, 13a, and 13b exhibited cytotoxic activities with promising IC50 values of 2.67, 6.21, 1.07 μM against MCF-7 cells and 3.21, 8.91, 0.32 μM against HepG2 cells compared to Erlotinib (IC50 = 2.51, 2.91 μM, respectively) as reference drug. Interestingly, compounds 13b induced apoptosis in MCf-7 and HepG2 cells, arresting the cell cycle at the G2/M and S phases, respectively. Additionally, the dual enzyme inhibition seen in compound 13b against EGFR and PARP-1 is encouraging, with IC50 values of 62.4 nM compared to Erlotinib (80 nM) and 1.24 nM compared to Olaparib (1.49 nM), respectively. The anticancer activity was finally validated using an in vivo SEC-cancer model; compound 13b improved both hematological and biochemical analyses inhibiting tumor proliferation by 66.7% compared to Erlotinib’s 65.7%. So, compound 13b may serve as a promising anticancer activity through dual PARP-1/EGFR target inhibition.