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A novel series of 2-arylbenzothiazoles 9, 10, and 12 were designed and synthesized as VEGFR-2/FGFR-1/PDGFR-β multiangiokinase inhibitors targeting breast cancer. Structural elongation of the known 2-phenylbenzothiazole scaffold (type I protein kinase inhibitor [PKI]), was carried out to afford series of type II PKIs 9, 10, and 12. Compounds 9d, 9f, 9i, and 9k exhibited potent multikinase inhibitory activity with IC50 values of 0.19, 0.18, 0.17, and 0.13 μM, respectively, against VEGFR-2; IC50 values of 0.28, 0.37, 0.19, and 0.27 μM, respectively, against FGFR-1; and IC50 values of 0.07, 0.04, 0.08, and 0.14 μM, respectively, against PDGFR-β. Moreover, the synthesized benzothiazoles demonstrated promising cytotoxic activity against the MCF-7 cell line. The most potent benzothiazoles 9d and 9i exhibited IC50 values of 7.83 and 6.58 μM, respectively, on the MCF-7 cell line in comparison to sorafenib (III), which showed IC50  = 4.33 μM. Additionally, 9d and 9i showed VEGFR-2 inhibitory activity in MCF-7 cells of 81% and 83% when compared with sorafenib (III), which showed 88% inhibition. Molecular docking of the designed compounds in the VEGFR-2 and FGFR-1 active sites showed the accommodation of the 2-phenylbenzothiazole moiety, as reported, in the hinge region of the receptor tyrosine kinase (RTK)-binding site, while the amide moiety is involved in hydrogen bond interactions with the key amino acids in the gate area; this in turn directs the aryl group to the hydrophobic allosteric back pocket of the RTKs in a type II-like binding mode. The synthesized benzothiazoles showed satisfactory ADME properties for further optimization in drug discovery. © 2020 Deutsche Pharmazeutische Gesellschaft.


Heba T Abdel-Mohsen, Eman A Abd El-Meguid, Ahmed M El Kerdawy, Abeer E E Mahmoud, Mamdouh M Ali. Design, synthesis, and molecular docking of novel 2-arylbenzothiazole multiangiokinase inhibitors targeting breast cancer. Archiv der Pharmazie. 2020 Apr;353(4):e1900340

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PMID: 32045054

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