Design and synthesis of new bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazines) and bis((quinoxalin-2-yl)phenoxy)alkanes as anti-breast cancer agents through dual PARP-1 and EGFR targets inhibition

Abstract

A number of new 1,ω-bis((acetylphenoxy)acetamide)alkanes 5a–f were prepared then their bromination using NBS furnished the novel bis(2-bromoacetyl)phenoxy)acetamides 6a–f. Reaction of 6a–f with 4-amino-5-substituted-4H-1,2,4-triazole-3-thiol 7a–d and with o-phenylenediamine derivatives 9a and b afforded the corresponding bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazine) derivatives 8a–l and bis(quinoxaline) derivatives 10a–e in good yields. The cytotoxicity of the synthesized compounds as well as apoptosis induction through PARP-1 and EGFR as molecular targets was evaluated. Three compounds, 8d, 8i and 8l, exhibited much better cytotoxic activities against MDA-MB-231 than the drug Erlotinib. Interestingly, compound 8i induced apoptosis in MDA-MB-231 cells by 38-fold compared to the control arresting the cell cycle at the G2/M phase, and its treatment upregulated P53, Bax, caspase-3, caspase-8, and caspase-9 gene levels, while it downregulated the Bcl2 level. Compound 8i exhibited promising dual enzyme inhibition of PARP-1 (IC₅₀ = 1.37 nM) compared to Olaparib (IC₅₀ = 1.49 nM), and EGFR (IC₅₀ = 64.65 nM) compared to Erlotinib (IC₅₀ = 80 nM). These results agreed with the molecular docking studies that highlighted the binding disposition of compound 8i inside the PARP-1 and EGFR protein active sites. Hence, compound 8i may serve as a potential anti-breast cancer agent.