Novel imidazo[2,1-b]thiazoles and imidazo[1,2-a]pyridines tethered with indolinone motif as VEGFR-2 inhibitors and apoptotic inducers: Design, synthesis and biological evaluations.

Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE

Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.

Vascular Endothelial Growth Factor Receptor-2*/antagonists & inhibitors ; Vascular Endothelial Growth Factor Receptor-2*/metabolism ; Pyridines*/chemistry ; Pyridines*/pharmacology ; Pyridines*/chemical synthesis ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemical synthesis ; Antineoplastic Agents*/chemistry ; Drug Design* ; Drug Screening Assays, Antitumor* ; Protein Kinase Inhibitors*/pharmacology ; Protein Kinase Inhibitors*/chemical synthesis ; Protein Kinase Inhibitors*/chemistry ; Thiazoles*/chemistry ; Thiazoles*/pharmacology ; Thiazoles*/chemical synthesis ; Apoptosis*/drug effects ; Cell Proliferation*/drug effects ; Dose-Response Relationship, Drug*; Humans ; Structure-Activity Relationship ; Molecular Structure ; Molecular Docking Simulation ; Cell Line, Tumor ; Imidazoles/chemistry ; Imidazoles/pharmacology ; Imidazoles/chemical synthesis ; Indoles/chemistry ; Indoles/pharmacology ; Indoles/chemical synthesis

The current study investigates the anticancer and VEGFR-2 inhibitory activities of 16 novel indolinone-grafted imidazo[2,1-b]thiazole and imidazo[1,2-a]pyridine derivatives (6a-h and 10a-h). The structures of these target compounds were confirmed using elemental and spectral analyses. All compounds were evaluated for their VEGFR-2 inhibitory activity in vitro, with eight compounds demonstrating promising results, exhibiting IC 50 values in the sub-micromolar range (0.22 μM - 0.95 μM). Additionally, the anticancer potential of these compounds was assessed using an MTT assay against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compounds 6a, 6f, 6 h, and 10f showed superior performance (IC 50  = 9.79, 8.78, 8.35, and 10.88 µM, respectively) compared to the reference drug cisplatin (IC 50  = 11.50 µM) against MDA-MB-231 cells. Based on their consistent VEGFR-2 inhibitory activity, compounds 6a, 6 h, and 10f were selected for further analysis. Molecular docking studies with VEGFR-2 (PDB ID: 4AGD) revealed binding behaviors similar to the co-crystallized ligand sunitinib. Among the reported target molecules, compound 10f exhibited the most desirable characteristics in terms of efficacy and safety and was further analyzed using density-functional theory (DFT) simulations to better understand its physical properties.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)

Keywords: Anticancer; DFT; Kinase inhibitor; Molecular modeling; Synthesis

EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
0 (Pyridines)
0 (Antineoplastic Agents)
0 (Protein Kinase Inhibitors)
EC 2.7.10.1 (KDR protein, human)
0 (Thiazoles)
0 (Imidazoles)
0 (Indoles)
0 (imidazo(2,1-b)thiazole)
G18ZBV2HXA (imidazo(1,2-a)pyridine)

Date Created: 20240730 Date Completed: 20240828 Latest Revision: 20240904

20240905

10.1016/j.bioorg.2024.107644

39079394