3′‐(4‐(Benzyloxy)phenyl)‐1′‐phenyl‐5‐(heteroaryl/aryl)‐3,4‐dihydro‐1′H,2H‐[3,4′‐bipyrazole]‐2‐carboxamides as EGFR kinase inhibitors: Synthesis, anticancer evaluation, and molecular docking studies

Abstract

Pyrazoline‐linked carboxamide derivatives were designed, synthesized, and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer activity, and apoptotic and cardiomyopathy toxicity. Compounds 6m and 6n inhibit EGFR kinase at a concentration of 6.5 ± 2.91 and 3.65 ± 0.54 µM, respectively. Some of these compounds showed effects on proliferation, which were also then evaluated against four different human cancer cell lines, that is, MCF‐7 (breast cancer), A549 (non‐small‐cell lung tumor), HCT‐116 (colon cancer), and SiHa cells (cancerous tissues of the cervix uteri). The results showed that certain synthetic compounds showed significant inhibitor activity; compounds 6m and 6n were more cytotoxic than doxorubicin against A549 cancer cells, with IC50 values of 10.3 ± 1.07 and 4.6 ± 0.57 µM, respectively. Additionally, compounds 6m and 6n induced apoptosis in A549 cancer cells, as evidenced by 4′,6‐diamidino‐2‐phenylindole (DAPI) staining and phase‐contrast microscopy. Potency to induce apoptosis by compound 6n was further confirmed by fluorescence‐activated cell sorting using Annexin V‐FITC and propidium iodide labeling. Compound 6n showed normal cardiomyocytes with no marked sign of pyknotic nuclei in cardiomyopathy and also normal histological appearance of the renal cortex when compared with that of control. Results of molecular docking studies suggested that compounds 6m and 6n can bind to the hinge region of the adenosine triphosphate‐binding site of EGFR kinase, like the standard drug erlotinib. Therefore, the present study suggests that compounds 6m and 6n have potent in vitro antitumor activities against the human non‐small‐cell lung tumor cell line A549, which can be further explored in other cancer cell lines and in animal studies.

Pyrazoline Hybrids as Promising Anticancer Agents: An Up-to-Date Overview

“…While keeping the core pyrazolyl pyrazoline structure unchanged, Nawaz et al introduced a bulky benzyloxy group in the place of NO 2 and Cl of the previous most active structures and a carboxamide group instead of an acetyl at nitrogen-1 of the pyrazoline aiming to develop EGFR kinase inhibitors [136]. Compound 60 (Figure 21…”

“…While keeping the core pyrazolyl pyrazoline structure unchanged, Nawaz et al introduced a bulky benzyloxy group in the place of NO 2 and Cl of the previous most active structures and a carboxamide group instead of an acetyl at nitrogen-1 of the pyrazoline aiming to develop EGFR kinase inhibitors [ 136 ]. Compound 60 ( Figure 21 ) was the most active (IC 50 3.65 μM), being at the same time the most potent against four different human cancer cell lines (IC 50 values of 6.5, 4.6, 12.6, and 40.8 μM against HCT-116, A549, MCF-7, and SiHa, respectively).…”

Design, synthesis, and biological evaluation of imidazopyridine‐linked thiazolidinone as potential anticancer agents

“…As EGFR plays a role in multiple signaling pathways such as cell proliferation, angiogenesis, tumor growth, and metastasis, it is considered as a promising target for anticancer therapy. [ 49–51 ] Docking studies were performed to study the molecular binding pattern of synthesized imidazopyridine‐linked thiazolidinone derivatives within the active pocket of the crystal structure of EGFR (PDB ID: 3W2S) using Schrodinger program Maestro 10.5. The crystal structure of EGFR (3W2S) is selected for the docking study due to its high resolution (1.9 Å), ability to form important water‐mediated interactions with the ligand and amino acid Thr 790 residue, as well as its ability to form essential hydrogen bonds with amino acids like Met 793.…”

“…The crystal structure of EGFR (3W2S) is selected for the docking study due to its high resolution (1.9 Å), ability to form important water‐mediated interactions with the ligand and amino acid Thr 790 residue, as well as its ability to form essential hydrogen bonds with amino acids like Met 793. [ 51,63,64 ] Several interactions such as hydrogen bond, hydrophobic interactions, π interaction, and so forth, with the active pocket of the targeted enzyme, were considered for the docking score of the synthesized compounds. The docking score, binding energies, and types of interactions of all the synthesized compounds are presented in Table 3.…”

Synthetic Routes to Bioactive Bipyrazole Derivatives

“…Pyrazole‐carbaldehyde 99 underwent Claisen–Schmidt condensation with substituted acetophenone to afford pyrazole‐chalcone conjugates 100 . Treatment of 5 with semicarbazide or thiosemicarbazide in ethanol and sodium hydroxide afforded the 3,4′‐bipyrazole derivatives 101 in 56–77 % yields [71,72] . The prepared bipyrazoles 101 exhibited potent anticancer activity against four human cancer cell lines and were more cytotoxic than doxorubicin against A549 cancer cell.…”