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

Abstract

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.