Design and synthesis of novel isatin-isoniazidhydrazone hybrid-based 1,2,3-triazoles as dual EGFR/PARP-1 inhibitors and apoptosis inducers in breast cancer cells

In this study, an efficient click synthesis has been employed to combine isatin, Schiff base, and 1,2,3-triazole in a single framework. Propargylation of 5-bromoisatin, followed by condensation with isoniazid, furnished the corresponding isatin-isoniazid hydrazone-based alkyne intermediate. Subsequent CuAAC reaction with a series of aromatic azides afforded a library of 1,2,3-triazole derivatives incorporating isatin-isoniazid hydrazone conjugates. The synthesized click adducts were characterized using the appropriate spectroscopic techniques, including ¹H, ¹³C, and ¹⁹F NMR, and HRMS. They were also subjected to dual EGFR/PARP-1 inhibition and cytotoxic screening in MDA-MB-231 TNBC cells, and Apoptosis induction was assessed by flow cytometry and RT-PCR. Compounds 9, 10, and 11 exhibited IC₅₀ values of 93, 64, and 78 nM, respectively, compared to Erlotinib (IC₅₀ = 80 nM); they exhibited IC₅₀ values of 76, 12, and 28 nM, respectively, compared to Olaparib (IC₅₀ = 12 nM). They showed potent cytotoxicity against MDA-MB-231 cells with IC₅₀ values of 16.3 ± 0.4, 1.27 ± 0.1, and 3.46 ± 0.1 μM, respectively. However, when tested against normal MCF-10 A cells, they showed low cytotoxicity and greater IC₅₀ values. The cell cycle was halted at the G2-phase by compound 10, which promoted Apoptosis 7.16-fold. The MDA-MB-231 Cancer cells' apoptosis-related genes were impacted. Molecular docking analysis revealed good binding disposition of compound 10 to the two EGFR/PARP-1 target proteins.