Building on our previous research on edaravone-derived bioactive small molecules, the precursors 2-5 were synthesized by condensation reactions between 4-{[(4-acetylphenyl)amino]methylidene}-5-methyl-2-phenylpyrazol-3-one (1) and a variety of organic hydrazines. Next, diversity-oriented S, N-heterocyclization of 2 was employed to access N-phenylpyrazolone-N-benzylthiazole hybrids bearing an azo phenyl fragment (6a,b) and N-phenylpyrazolone-N-benzyl-4-thiazolone hybrids linked to an acrylate unit (7a,b). S, N-heterocyclization to access 6a,b was started by Williamson thioether synthesis between 2 and arene hydrazonoyl halides, while in 7a,b it was commenced via 1,4-thia-Michael addition between 2 and activated alkynes. The molecular structures of these uncommon hybrids were confirmed by instrumental analyses. Their cytotoxicity activity against osteosarcoma (Hos), non-small lung (A549), and colon carcinoma (HCT-116) cancer cell lines was tested via MTT bioassay using doxorubicin as a medical reference. The precursor 4 that bears a sulfonamide fragment is the sole molecule that is cytotoxic against all the tested cell lines, with an IC50 order of HCT-116 (7.3 ± 0.47) > A549 (20.4 ± 0.55) > Hos (39.9 ± 0.07 µM). The ELISA kit showed that 4 impacted the pRIPK3 kinase concentration in the A549 (2.97 ± 0.010 pg/mL), but less than DMSO-treated cells (2.93 ± 0.010 pg/mL). The best docking mode of 4with RIPK3 (7MX3) displayed two H-bonds and some hydrophobic interactions with a fitness energy of -116.704 kcal/mol, which is higher than the lead compound (-123.382 kcal/mol) that was documented in our earlier study8, validating the experimental results and suggesting 4 as a suitable candidate for structure modification and further biological investigations owing to the presence of the sulfonamide unit.
