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. 2022 Jul 27;12(1):12821.
doi: 10.1038/s41598-022-15050-8.

Design, synthesis, in vitro biological assessment and molecular modeling insights for novel 3-(naphthalen-1-yl)-4,5-dihydropyrazoles as anticancer agents with potential EGFR inhibitory activity

Wagdy M Eldehna  1   2 , Mahmoud A El Hassab  3 , Zainab M Elsayed  4 , Tarfah Al-Warhi  5 , Hazem Elkady  6 , Mahmoud F Abo-Ashour  7 , Mohammed A S Abourehab  8 , Ibrahim H Eissa  6 , Hatem A Abdel-Aziz  9
Affiliations

Design, synthesis, in vitro biological assessment and molecular modeling insights for novel 3-(naphthalen-1-yl)-4,5-dihydropyrazoles as anticancer agents with potential EGFR inhibitory activity

Wagdy M Eldehna et al. Sci Rep. .

Abstract

Currently, the humanity is in a fierce battle against various health-related challenges especially those associated with human malignancies. This created the urge to develop potent and selective inhibitors for tumor cells through targeting specific oncogenic proteins possessing crucial roles in cancer progression and survive. In this respect, new series of pyrazole-thiazol-4-one hybrids (9a-p) were synthesized as potential anticancer agents. All the synthesized molecules exhibited potent antiproliferative actions against breast cancer (BC) T-47D and MDA-MB-231 cell lines with IC50 ranges 3.14-4.92 and 0.62-58.01, respectively. Moreover, the most potent anti-proliferative counterparts 9g and 9k were assessed against EGFR. They displayed nanomolar inhibitory activity, IC50 267 ± 12 and 395 ± 17 nM, respectively. Worth noting, both compounds 9g and 9k induced apoptosis in MDA-MB-231 cells, and resulted in a cell cycle arrest at G2/M phase. Furthermore, an in silico analysis including docking and molecular dynamic simulations was performed.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
(A) The reported pharmacophoric features of EGFRIs. (B) Reported FDA EGFR inhibitors (Gefitinib and Erlotinib) and the synthesized compounds in this study (9a-p), as well as the binding mode of Erlotinib within EGFR active site.
Scheme 1
Scheme 1
Synthesis of target molecules 9a-p; (i) 40% sodium hydroxide, 95% ethyl alcohol, stirring at R.T. 8 h; (ii) Sodium hydroxide, ethyl alcohol, reflux 2 h; (iii) Absolute ethyl alcohol, sodium acetate, reflux 4 h; (iv) Glacial AcOH, CH3COONa, reflux 6 h.
Figure 2
Figure 2
Effect of 9g and 9k on the phases of cell cycle of MDA-MB-231 cells.
Figure 3
Figure 3
Effect of pyrazolines 9g and 9k on the percentage of annexin V-FITC-positive staining in MDA-MB-231 cells.
Figure 4
Figure 4
The binding mode of the crystal reference erlotinib with the EGFR receptor.
Figure 5
Figure 5
The 2D interaction diagram of EGFR receptor with 9g (left) 9k (right).
Figure 6
Figure 6
The 3D interaction diagram of EGFR receptor with 9g (left) 9k (right).
Figure 7
Figure 7
RMSD analysis for the MD simulations.
Figure 8
Figure 8
The RMSF analysis for the MD simulations.
Figure 9
Figure 9
The per residue contribution for the binding free energy of 9g and 9k with EGFR.
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