2. Academic Validation
  3. Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation

Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation

  • Bioorg Med Chem Lett. 2024 Feb 24:102:129673. doi: 10.1016/j.bmcl.2024.129673.
Osama M Soltan 1,  Salah A Abdel-Aziz 2,  Montaser Sh Shaykoon 1,  Keima Osawa 3,  Atsushi Narumi 4,  Mohamed Abdel-Aziz 5,  Mai E Shoman 5,  Hiroyuki Konno 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, 61111 Minia, Egypt.
  • 3 Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Jonan 4-3-16, Yonezawa, Yamagata 992-8510, Japan.
  • 4 Department of Organic Materials Science, Graduate School of Organic Materials Science, Yamagata University, Jonan 4-3-16, Yonezawa, Yamagata 992-8510, Japan.
  • 5 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.
  • 6 Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Jonan 4-3-16, Yonezawa, Yamagata 992-8510, Japan. Electronic address: konno@yz.yamagata-u.ac.jp.
PMID: 38408511 DOI: 10.1016/j.bmcl.2024.129673
Abstract

The eradication of multifactorial diseases, such as Cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible Anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 Cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC50) values of 2.7-63 μM. The tests confirmed that 5b and 5d were potent JNK-2 inhibitors, with IC50 of 2.0 and 0.9 μM, respectively, whereas 6 h selectively inhibited EGFR protein kinase (EGFR-PK) (IC50 = 1.7 μM). Notably, 6c inhibited both kinases, with IC50 values of 2.7 and 3.0 μM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce Apoptosis and induce cell cycle arrest at different cell phases.

Keywords

Anticancer; Diaryl pyrazoles; EGFR inhibitors; JNK-2 inhibitors; Multi-kinase inhibitors.

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