Development and Assessment of 1,5-Diarylpyrazole/Oxime Hybrids Targeting EGFR and JNK-2 as Antiproliferative Agents: A Comprehensive Study through Synthesis, Molecular Docking, and Evaluation.

New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds and ) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds -, -, -, and -. The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds , , , and inhibited EGFR with IC values ranging from 8 to 21 µM when compared with sorafenib. Compound inhibited JNK-2 as effectively as sorafenib, with an IC of 1.0 µM. Furthermore, compound showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds , , , and exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds and had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.