Analogue-based Design, Synthesis, Characterisation and Computational Studies of Novel Aminopyrimidine-Phenyl Urea Derivatives as Prospective Dual VEGFR/RAF-Kinase Inhibitors

Al Yasiri, Mohammed; MalUllah, Amjed; Al-Fahad, Dhurgham; Jassim, Nawras

doi:10.22075/chem.2026.41646.2461

Analogue-based Design, Synthesis, Characterisation and Computational Studies of Novel Aminopyrimidine-Phenyl Urea Derivatives as Prospective Dual VEGFR/RAF-Kinase Inhibitors

مقالات آماده انتشار

نوع مقاله : مقاله علمی پژوهشی

نویسندگان

Mohammed Al Yasiri ¹

Amjed MalUllah ²

Dhurgham Al-Fahad ³

Nawras Jassim ⁴

¹ Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq.

² Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq

³ Department of Pathological Analysis, College of Science, University of Thi-Qar, Iraq

⁴ Department of Organic Chemistry and Technologies, Kuban State University, Russia

10.22075/chem.2026.41646.2461

چکیده

Recently, there has been attention on the design and synthesis of dual inhibitors targeting both VEGFR and RAF kinases, which may offer improved efficacy and reduced resistance compared with traditional single-target therapies. This study reports the development of a series of urea derivatives featuring aminopyrimidine-phenyl moieties designed as potential dual inhibitors. The synthesised compounds were characterised by 1H NMR, 13C NMR, and FT-IR spectral techniques. Furthermore, molecular docking analyses utilizing MOE software were conducted to evaluate the binding interactions of these compounds with target protein residues, indicating comparable interactions to the reference ligand and favorable energy scores with the active sites of VEGFR and B-RAF proteins. To confirm the stability of the protein-ligand complexes, molecular dynamics simulations were performed, revealing stable associations between the compounds and the VEGFR and B-Raf structures through analyses of RMSD, RMSF, RoG, and hydrogen bonds. The DFT parameters indicate that the synthesized compounds possess favorable electronic properties, substantial charge-transfer capability, and elevated reactivity. Among these, compound 12 was identified as the most potent candidate against VEGFR and B-RAF proteins. Additionally, in silico predictions for absorption, distribution, metabolism, excretion, and toxicities (ADMET) showed that all compounds fall within an acceptable drug-likeness range. Future work will involve examining the anticancer activities of these compounds in vitro and in vivo.

کلیدواژه‌ها

Urea Derivatives

Dual Inhibitors

VEGFR/RAF Kinases

Molecular Docking

Dynamic Simulation

موضوعات