New edaravone analogs incorporated with N‐benzylthiazole moiety: Multistep chemical synthesis, in vitro cytotoxicity with pRIPK3 inhibitory activities, and molecular docking

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AbstractIn this research article, the chemical synthesis of new N‐phenylpyrazolone‐N‐benzylthiazole hybrids (3–6) via late‐stage thiazolation of the corresponding benzylthiosemicarbazone 2 was reported. The skeletal structural of the new molecules were validated by instrumental measurements (FT‐IR, NMR, and EI‐MS). In vitro cytotoxicity‐based cellular MTT bioassay shows that compound 3 that bears an N‐benzyl‐4‐thiazolone moiety is the most potent one toward the osteosarcoma cell line (Hos) with an IC50 value of 5.8 ± 0.1 μM, while compound 4a that contains a 5‐acetyl‐N‐benzylthiazole unit is the most robust one against the model lung carcinoma cell line (A549) with an IC50 value of 9.23 ± 0.01 μM. Also, 3 is roughly equipotent to 4b in its cytotoxicity activity against A549. In vitro enzymatic ELISA bioassay of A549 cells indicates that IC50 of 3 caused a decrease in the pRIPK3 kinase concentration (2.89 ± 0.005 pg/mL) as compared to DMSO‐treated cells (2.93 ± 0.010 pg/mL), while the pRIPK3 level incresed with 4b impact. As a result, 3 may be an effective inhibitor of pRIPK3 and hence necroptosis, proposing a novel therapeutic strategy for necroptosis‐related illnesses. In silico molecular docking shows that 3 interlocked and fitted well into the binding site of RIPK3 (PDB code: 7MX3) with a fitness value (−123.382 kcal/mol) lower than 4b and forms an important H‐bond with Lys50 like the marketed RIPK3 inhibitor GSK'843, validating the experimental results. Consequently, 3 is the most promising molecule that could be a lead candidate for further studies.