Novel 4-(2-arylidenehydrazineyl)thienopyrimidine derivatives as anticancer EGFR inhibitors: Design, synthesis, biological evaluation, kinome selectivity and in silico insights

Heba A Elsebaie; Eman A El-Bastawissy; Kamel M Elberembally; Eman F Khaleel; Rehab Mustafa Badi; Moataz A Shaldam; Wagdy M Eldehna; Haytham O Tawfik; Tarek F El-Moselhy

doi:10.1016/j.bioorg.2023.106799

Novel 4-(2-arylidenehydrazineyl)thienopyrimidine derivatives as anticancer EGFR inhibitors: Design, synthesis, biological evaluation, kinome selectivity and in silico insights

Bioorg Chem. 2023 Nov:140:106799. doi: 10.1016/j.bioorg.2023.106799. Epub 2023 Aug 22.

Authors

Heba A Elsebaie¹, Eman A El-Bastawissy², Kamel M Elberembally³, Eman F Khaleel⁴, Rehab Mustafa Badi⁵, Moataz A Shaldam⁶, Wagdy M Eldehna⁷, Haytham O Tawfik⁸, Tarek F El-Moselhy⁹

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527 Egypt. Electronic address: heba.nseer@pharm.tanta.edu.eg.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527 Egypt. Electronic address: emanesmat@pharm.tanta.edu.eg.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527 Egypt. Electronic address: kamel.mohamed@pharm.tanta.edu.eg.
⁴ Department of Medical Physiology, College of Medicine, King Khalid University, King Khalid University, Asir 61421, Saudi Arabia. Electronic address: eman_4000@hotmail.com.
⁵ Department of Medical Physiology, College of Medicine, King Khalid University, King Khalid University, Asir 61421, Saudi Arabia. Electronic address: rbadi@kku.edu.sa.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt. Electronic address: dr_moutaz_986@pharm.kfs.edu.eg.
⁷ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt; School of Biotechnology, Badr University in Cairo, Badr City 11829, Egypt. Electronic address: wagdy2000@gmail.com.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527 Egypt. Electronic address: haytham.omar.mahmoud@pharm.tanta.edu.eg.
⁹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527 Egypt. Electronic address: tarek.faathy@pharm.tanta.edu.eg.

PMID: 37625210
DOI: 10.1016/j.bioorg.2023.106799

Abstract

The current study discovered fifteen new thieno[2,3-d]pyrimidine derivatives with potential anticancer action, including 5a-l, 6, and 7a-b. Results from the NCI screening revealed that compounds 5f-i and 7a significantly inhibited the proliferation of MDA-MB-468 cells at mean GI% and GI₅₀ levels. Compared to staurosporine, these compounds (5f-i and 7a) demonstrated better safety towards typical WI-38 cells. Compounds 5g and 7a demonstrated the highest inhibition (two-digit nanomolar) when compared to erlotinib when their potency was tested on EGFR kinase. Considering the outcomes above, 5g was examined for its ability to disrupt the cell cycle with trigger apoptosis in breast cancer MDA-MB-468 cell lines. The apoptosis markers Bax, Bcl-2, Caspase-8, and Caspase-9, were detected. In silico molecular docking and dynamic simulation were used to explainthe biological activities of the most potent compound.

Keywords: Anticancer; EGFR kinase inhibitors; Gewald; Selectivity; Thienopyrimidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antihypertensive Agents*
Apoptosis*
ErbB Receptors
Molecular Docking Simulation

Substances

thienopyrimidine
Antihypertensive Agents
ErbB Receptors