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Design, synthesis, and molecular docking of novel 2‐arylbenzothiazole multiangiokinase inhibitors targeting breast cancer
Author(s) -
AbdelMohsen Heba T.,
Abd ElMeguid Eman A.,
El Kerdawy Ahmed M.,
Mahmoud Abeer E. E.,
Ali Mamdouh M.
Publication year - 2020
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201900340
Subject(s) - chemistry , moiety , sorafenib , docking (animal) , stereochemistry , hydantoin , kinase , cell culture , allosteric regulation , receptor , cancer research , biochemistry , biology , medicine , genetics , nursing , hepatocellular carcinoma
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 IC 50 values of 0.19, 0.18, 0.17, and 0.13 μM, respectively, against VEGFR‐2; IC 50 values of 0.28, 0.37, 0.19, and 0.27 μM, respectively, against FGFR‐1; and IC 50 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 IC 50 values of 7.83 and 6.58 μM, respectively, on the MCF‐7 cell line in comparison to sorafenib ( III ), which showed IC 50 = 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.