Quinazolin-4-one/3-cyanopyridin-2-one Hybrids as Dual Inhibitors of EGFR and BRAFV600E: Design, Synthesis, and Antiproliferative Activity

Lamya H Al-Wahaibi; Mohamed Hisham; Hesham A Abou-Zied; Heba A Hassan; Bahaa G M Youssif; Stefan Bräse; Alaa M Hayallah; Mohamed Abdel-Aziz

doi:10.3390/ph16111522

Quinazolin-4-one/3-cyanopyridin-2-one Hybrids as Dual Inhibitors of EGFR and BRAF^V600E: Design, Synthesis, and Antiproliferative Activity

Pharmaceuticals (Basel). 2023 Oct 26;16(11):1522. doi: 10.3390/ph16111522.

Authors

Lamya H Al-Wahaibi¹, Mohamed Hisham², Hesham A Abou-Zied², Heba A Hassan³, Bahaa G M Youssif⁴, Stefan Bräse⁵, Alaa M Hayallah^{4

6}, Mohamed Abdel-Aziz³

Affiliations

¹ Department of Chemistry, College of Sciences, Princess Nourah Bint Abdulrahman University, Riyadh 11564, Saudi Arabia.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Universities Zone, New Minia City 61111, Egypt.
³ Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
⁴ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
⁵ Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
⁶ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Sphinx University, Assiut 71515, Egypt.

Abstract

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAF^V600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI₅₀ values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI₅₀ = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAF^V600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAF^V600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects.

Keywords: 3-cyanopyridin-2-one; BRAFV600E; EGFR; anti-cancer; docking; quinazolin-4-one.

Grants and funding

PNURSP2023R3/Princess Nourah bint Abdulrahman University