Design and Synthesis of New 1,2,4-oxadiazole/quinazoline-4-one Hybrids with Antiproliferative Activity As Multitargeted Inhibitors

Overview

Journal Front Chem

Specialty Chemistry

Date 2024 Sep 16

PMID 39281035

Authors

Amira M Mohamed

Ola M F Abou-Ghadir

Yaser A Mostafa

Kholood A Dahlous

Stefan Brase

Bahaa G M Youssif

Affiliations

Soon will be listed here.

Abstract

Introduction: The combination of BRAF and tyrosine kinase (TK) inhibitors has been demonstrated to be highly effective in inhibiting tumor development and is an approach for overcoming resistance in clinical trials. Accordingly, a novel series of 1,2,4-oxadiazole/quinazoline-4-one hybrids was developed as antiproliferative multitargeted inhibitors.

Methods: The structures of the newly synthesized compounds 9a-o were validated using IR, NMR, MS, and elemental techniques. 9a-o were tested as antiproliferative agents.

Results And Discussion: The results showed that the majority of the tested compounds showed significant antiproliferative action with 9b, 9c, 9h, 9k, and 9l being the most potent. Compounds 9b, 9c, 9h, 9k, and 9l were tested as EGFR and BRAF inhibitors. These tests revealed that compounds 9b, 9c, and 9h are strong antiproliferative agents that may act as dual EGFR/BRAF inhibitors. 9b, 9c, and 9h were further investigated for their inhibitory effect on mutant EGFR (EGFR), and the results showed that the tested compounds had considerable inhibitory action. Cell cycle study and apoptosis detection demonstrated that compound 9b exhibits cell cycle arrest at the G2/M transition. Molecular docking simulations reveal the binding mechanism of the most active antiproliferative agents.

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References

Al-Wahaibi L, El-Sheref E, Hassan A, Brase S, Nieger M, Youssif B . Synthesis and Structure Determination of Substituted Thiazole Derivatives as EGFR/BRAF Dual Inhibitors Endowed with Antiproliferative Activity. Pharmaceuticals (Basel). 2023; 16(7). PMC: 10384562. DOI: 10.3390/ph16071014. View

Padwa A, Bur S . The Domino Way to Heterocycles. Tetrahedron. 2007; 63(25):5341-5378. PMC: 2031872. DOI: 10.1016/j.tet.2007.03.158. View

Umar A, Uzairu A, Shallangwa G, Uba S . QSAR modelling and molecular docking studies for anti-cancer compounds against melanoma cell line SK-MEL-2. Heliyon. 2020; 6(3):e03640. PMC: 7110328. DOI: 10.1016/j.heliyon.2020.e03640. View

Youssif B, Mohamed M, Al-Sanea M, Moustafa A, Abdelhamid A, Gomaa H . Novel aryl carboximidamide and 3-aryl-1,2,4-oxadiazole analogues of naproxen as dual selective COX-2/15-LOX inhibitors: Design, synthesis and docking studies. Bioorg Chem. 2019; 85:577-584. DOI: 10.1016/j.bioorg.2019.02.043. View

Al-Wahaibi L, Mostafa Y, Abdelrahman M, El-Bahrawy A, Trembleau L, Youssif B . Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors. Pharmaceuticals (Basel). 2022; 15(8). PMC: 9414584. DOI: 10.3390/ph15081006. View

El-Sherief H, Youssif B, Bukhari S, Abdelazeem A, Abdel-Aziz M, Abdel-Rahman H . Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors. Eur J Med Chem. 2018; 156:774-789. DOI: 10.1016/j.ejmech.2018.07.024. View

Mahmoud M, Mohammed A, Salem O, Gomaa H, Youssif B . New 1,3,4-oxadiazoles linked with the 1,2,3-triazole moiety as antiproliferative agents targeting the EGFR tyrosine kinase. Arch Pharm (Weinheim). 2022; 355(6):e2200009. DOI: 10.1002/ardp.202200009. View

El Mansouri A, Oubella A, Maatallah M, AitItto M, Zahouily M, Morjani H . Design, synthesis, biological evaluation and molecular docking of new uracil analogs-1,2,4-oxadiazole hybrids as potential anticancer agents. Bioorg Med Chem Lett. 2020; 30(19):127438. DOI: 10.1016/j.bmcl.2020.127438. View

Mekheimer R, Allam S, Al-Sheikh M, Moustafa M, Al-Mousawi S, Mostafa Y . Discovery of new pyrimido[5,4-c]quinolines as potential antiproliferative agents with multitarget actions: Rapid synthesis, docking, and ADME studies. Bioorg Chem. 2022; 121:105693. DOI: 10.1016/j.bioorg.2022.105693. View

10.

Derbyshire E, Mazitschek R, Clardy J . Characterization of Plasmodium liver stage inhibition by halofuginone. ChemMedChem. 2012; 7(5):844-9. PMC: 3359061. DOI: 10.1002/cmdc.201200045. View

11.

Zhou J, Jiang X, He S, Jiang H, Feng F, Liu W . Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms. J Med Chem. 2019; 62(20):8881-8914. DOI: 10.1021/acs.jmedchem.9b00017. View

12.

Al-Wahaibi L, Abou-Zied H, Hisham M, Beshr E, Youssif B, Brase S . Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAF Inhibitory Pathways. Molecules. 2023; 28(18). PMC: 10537368. DOI: 10.3390/molecules28186586. View

13.

Okaniwa M, Hirose M, Imada T, Ohashi T, Hayashi Y, Miyazaki T . Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds. J Med Chem. 2012; 55(7):3452-78. DOI: 10.1021/jm300126x. View

14.

Fu R, Sun Y, Sheng W, Liao D . Designing multi-targeted agents: An emerging anticancer drug discovery paradigm. Eur J Med Chem. 2017; 136:195-211. DOI: 10.1016/j.ejmech.2017.05.016. View

15.

Abou-Zied H, Beshr E, Gomaa H, Mostafa Y, Youssif B, Hayallah A . Discovery of new cyanopyridine/chalcone hybrids as dual inhibitors of EGFR/BRAF with promising antiproliferative properties. Arch Pharm (Weinheim). 2022; 356(4):e2200464. DOI: 10.1002/ardp.202200464. View

16.

Al-Wahaibi L, El-Sheref E, Hammouda M, Youssif B . One-Pot Synthesis of 1-Thia-4-azaspiro[4.4/5]alkan-3-ones via Schiff Base: Design, Synthesis, and Apoptotic Antiproliferative Properties of Dual EGFR/BRAF Inhibitors. Pharmaceuticals (Basel). 2023; 16(3). PMC: 10056593. DOI: 10.3390/ph16030467. View

17.

Loboda K, Valjavec K, Stampar M, Wolber G, Zegura B, Filipic M . Design and synthesis of 3,5-substituted 1,2,4-oxadiazoles as catalytic inhibitors of human DNA topoisomerase IIα. Bioorg Chem. 2020; 99:103828. DOI: 10.1016/j.bioorg.2020.103828. View

18.

Al-Wahaibi L, Mahmoud M, Mostafa Y, Raslan A, Youssif B . Novel piperine-carboximidamide hybrids: design, synthesis, and antiproliferative activity via a multi-targeted inhibitory pathway. J Enzyme Inhib Med Chem. 2022; 38(1):376-386. PMC: 9721426. DOI: 10.1080/14756366.2022.2151593. View

19.

Moussa G, Alaaeddine R, Alaeddine L, Nassra R, Belal A, Ismail A . Novel click modifiable thioquinazolinones as anti-inflammatory agents: Design, synthesis, biological evaluation and docking study. Eur J Med Chem. 2018; 144:635-650. DOI: 10.1016/j.ejmech.2017.12.065. View

20.

Notarangelo T, Sisinni L, Condelli V, Landriscina M . Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells. Cancer Cell Int. 2017; 17:86. PMC: 5628448. DOI: 10.1186/s12935-017-0457-z. View