Design, Synthesis, Molecular Modeling and Biological Evaluation of Novel 1,5-Diarylpyrazole Carboxamide Derivatives as Antiproliferative Agents

Abstract

A series of novel 1,5-diarylpyrazole carboxamide derivatives was designed and synthesized. All the synthesized compounds were biologically evaluated for their in vitro cytotoxic activities against a panel of five cancer cell lines namely, DLD, Hela, K-562, SUIT and HepG-2. The results revealed that compound 5c exhibited the most prominent cytotoxic effect against four tested cell lines with growth inhibition percentages ranged from 75.95 to 123 % and IC50 values of 17.20 and 21.20 μM comparable to that of daunorubicin as a control drug (IC50 values of 13.30 and 22 μM) against K-562 and Hep-G2 cell lines, respectively. Molecular docking study suggested the ability of the tested compounds to inhibit EGFR-TK. Data showed that 5c possess the ability to bind to erlotinib binding site forming a stable complex with energy scores -7.73 compared to -7.63 for erlotinib. It potentially forms three hydrogen bonds with LYS 721 and GLU 638 residues. Data suggests that compound 5c is a promising lead in the design of further EGFR inhibitors.

Design, Synthesis, Anticancer Evaluation and Molecular Modeling Studies of New Thiazolidinone‐Benzoate Scaffold as EGFR Inhibitors, Cell Cycle Interruption and Apoptosis Inducers in HepG2

“…Moreover, the compounds 5 c and 5 h were evaluated for their effect on the cell cycle in HepG2 cell lines. The stages of cell cycle were detected through flow cytometry after propidium iodide (PI) staining [81] . From the obtained results in Table 3 and Figure 5, it was concluded that 5 c and 5 h caused interruption in the cell cycle progression in the treated HepG2 cells.…”

“…The stages of cell cycle were detected through flow cytometry after propidium iodide (PI) staining. [81] From the obtained results in Table 3 and Figure 5, it was concluded that 5 c and 5 h caused interruption in the cell cycle progression in the treated HepG2 cells. The change in the cell content % was detected in the treated cells with 5 c and 5 h compared to the control cells.…”

“…While the thiazolidinone derivative 5 h appeared to be active against EGFR kinase activity causing a potent activity giving IC 50 value; 0.098±0.004 μM that is about three folds lower than that of erlotinib. It could be noticed that the presence of donating substitution (OCH 3 ) in the pharmacophore of 5 c and 5 h caused a positive effect in the inhibition against EGFR kinase and the increase in the number of that kind of substitution in turn increased the inhibitory effect as seen in 5 h compared to the other functional group [81] …”

“…The cell death of HepG2 cell lines by apoptotic pathway induced by compound 5 c and 5 h was determined by annexin V/PI assay [81] . Annexin V‐FITC stain was used to stain cells with PI dye.…”

“…It could be noticed that the presence of donating substitution (OCH 3 ) in the pharmacophore of 5 c and 5 h caused a positive effect in the inhibition against EGFR kinase and the increase in the number of that kind of substitution in turn increased the inhibitory effect as seen in 5 h compared to the other functional group. [81]…”