Synthesis and Molecular Docking of Some Novel 3-Thiazolyl-Coumarins as Inhibitors of VEGFR-2 Kinase

Abstract

One crucial strategy for the treatment of breast cancer involves focusing on the Vascular Endothelial Growth Factor Receptor (VEGFR-2) signaling system. Consequently, the development of new (VEGFR-2) inhibitors is of the utmost importance. In this study, novel 3-thiazolhydrazinylcoumarins were designed and synthesized via the reaction of phenylazoacetylcoumarin with various hydrazonoyl halides and α-bromoketones. By using elemental and spectral analysis data (IR, 1H-NMR, 13C-NMR, and Mass), the ascribed structures for all newly synthesized compounds were clarified, and the mechanisms underlying their formation were delineated. The molecular docking studies of the resulting 6-(phenyldiazenyl)-2H-chromen-2-one (3, 6a–e, 10a–c and 12a–c) derivatives were assessed against VEGFR-2 and demonstrated comparable activities to that of Sorafenib (approved medicine) with compounds 6d and 6b showing the highest binding scores (−9.900 and −9.819 kcal/mol, respectively). The cytotoxicity of the most active thiazole derivatives 6d, 6b, 6c, 10c and 10a were investigated for their human breast cancer (MCF-7) cell line and normal cell line LLC-Mk2 using MTT assay and Sorafenib as the reference drug. The results revealed that compounds 6d and 6b exhibited greater anticancer activities (IC50 = 10.5 ± 0.71 and 11.2 ± 0.80 μM, respectively) than the Sorafenib reference drug (IC50 = 5.10 ± 0.49 μM). Therefore, the present study demonstrated that thiazolyl coumarins are potential (VEGFR-2) inhibitors and pave the way for the synthesis of additional libraries based on the reported scaffold, which could eventually lead to the development of efficient treatment for breast cancer.

Latest developments in coumarin-based anticancer agents: mechanism of action and structure–activity relationship studies

“…Several coumarin–thiazole derivatives were designed and synthesized and their cytotoxicity assessed on MCF-7 cancer cell lines using sorafenib as the reference drug. 100 Among them, 54a and 54b ( Fig. 49 ) demonstrated higher anticancer activities (IC 50 = 10.5 ± 0.71 and 11.2 ± 0.80 μM, respectively) than sorafenib (IC 50 = 5.10 ± 0.49 μM).…”

Hybrids based on coumarins and their anticancer activities: A bibliometric analysis

“…Binding interactions of coumarin derivatives with the active site of topoisomerase IIα, a key enzyme involved in DNA replication and transcription that is frequently overexpressed in cancer cells have been also investigated, revealing high binding affinity, thus potentially acting as topoisomerase inhibitors with anticancer activity (Gomaa et al, 2022). Abolibda et al (2023) evaluated the potential of novel coumarins derivatives as vascular endothelial growth factor receptor (VEGFR-2) inhibitors for the treatment of breast cancer, indicating comparable activities to that of Sorafenib as a reference drug. Triazole-coumarin-glycosyl hybrids and tetrazole hybrid analogs were synthesized, tested, and evaluated via molecular docking for the determination of binding affinity and targeted enzymes.…”

Mechanochemical Synthesis and Molecular Docking Studies of New Azines Bearing Indole as Anticancer Agents

“…Bearing the aforementioned in mind, and in the framework of our ongoing research on the synthesis of bioactive heterocyclic derivatives [42,[50][51][52][53][54][55][56][57][58][59], the goal of the present study is the green synthesis of some new aldazine and ketazine derivatives, starting with 3-(1-hydrazineylideneethyl)-1H-indole and the evaluation of their potential anticancer activities, which was further supported by molecular docking studies using EFP as a native ligand [48,49]. In addition, the drug-likeness as well as SAR analysis of the reported derivatives were also investigated.…”