Design, synthesis, molecular docking and biological evaluation of novel 1,5-diarylpyrazole-N,O-dimethyl hydroxamate derivatives as antiproliferative agents.

Abstract

A series of novel hybrid of 1,5-diarylpyrazole-N,O-dimethylhydroxamate derivatives were designed and synthesised in synthetically acceptable yields. All the new synthesized compounds were biologically evaluated for their in vitro cytotoxicity against a panel of five cell lines namely human colorectal adenocarcinoma cell line DLD1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cancer cell line Suit-2 and human hepatocellular carcinoma cell line HepG2. Compound 7a showed a significant cytotoxicity against Hela cell line with IC50 value of 16 µM and a good cytotoxicity against DLD1 and HepG2 with IC50 values of 69.9 µM and 78.8µM. Also, compound 7a displayed a potent EGFR inhibitory activity with IC50= 4.00 µM, which was comparable to positive reference drug sorafenib (IC50 = 3.5 µM). Moreover, in-silico studies showed that compound 7a has excellent binding affinity to the active site of EGFR with binding score better than a multitarget kinase drug sorafenib and good binding affinity to JNK-2, which explains the anticancer activity of compound 7a.