Synthesis, molecular docking and evaluation of 1,5-diarylpyrazole/oxime hybrids targeting EGFR and JNK-2 as antiproliferative agents

Abstract

Abstract A series of new 1,5-diarylpyrazole oxime hybrid derivatives (scaffold A and B) were designed, synthesized, and their structures were examined for purity with different spectroscopic techniques. All the synthesized compounds (7a-j), (8a-j), (9a-c) and (10a-c) were biologically evaluated for their in vitro cytotoxicity against a panel of five cancer cell lines known to express EGFR and JNK-2, namely 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. 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 8d, 8g, 8i, and 10c inhibited EGFR with IC50 values ranging from 8 to 21 µM when compared to sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC50 of 1.00 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the Hela cell line cell cycle analysis, whereas compound 8i showed combined S phase and G2 phase arrest. Docking studies revealed that oxime derivatives fit well at the EGFR binding site, with binding free energies ranging from -12.98 to 32.30 kcl/mol for compounds 8d, 8g, 8i, and 10c, while compounds 8d and 8i had binding free energies ranging from -9.16 to -12.00 kcl/mol at the JNK-2 binding site.