Premium
Pyridine‐derived VEGFR‐2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking
Author(s) -
Saleh Nashwa M.,
AbdelRahman Adel A.H.,
Omar Asmaa M.,
Khalifa Mohamed M.,
ElAdl Khaled
Publication year - 2021
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.202100085
Subject(s) - sorafenib , ic50 , doxorubicin , chemistry , cytotoxicity , stereochemistry , docking (animal) , pharmacology , cancer cell , cell culture , in vitro , biochemistry , cancer , biology , chemotherapy , medicine , cancer research , genetics , nursing , hepatocellular carcinoma
Novel pyridine‐derived compounds ( 5–19 ) were designed and synthesized, and their anticancer activities were evaluated against HepG2 and MCF‐7 cells, targeting the VEGFR‐2 enzyme. Compounds 10 , 9 , 8 , and 15 were found to be the most potent derivatives against the two cancer cell lines, HepG2 and MCF‐7, respectively, with IC 50 = 4.25 and 6.08 µM, 4.68 and 11.06 µM, 4.34 and 10.29 µM, and 6.37 and 12.83 µM. Compound 10 displayed higher activity against HepG2 cells than sorafenib (IC 50 = 9.18 and 5.47 µM, respectively) and doxorubicin (IC 50 = 7.94 and 8.07 µM, respectively). It also showed higher activity than doxorubicin against MCF‐7 cells, but lower activity than sorafenib. Compounds 9 , 8 , and 15 displayed higher activities than sorafenib and doxorubicin against HepG2 cells but exhibited lower activities against MCF‐7 cells. Compound 10 potently inhibited VEGFR‐2 at an IC 50 value of 0.12 µM, which is nearly equipotent to sorafenib (IC 50 = 0.10 µM). Compounds 8 and 9 exhibited very good activity with the same IC 50 value of 0.13 µM. The six most potent derivatives, 6 , 9 , 8 , 10 , 15 , and 18 , were tested for their cytotoxicity against normal Vero cells. Compounds 6 , 8 , 9 , 10 , 15 , and 18 are, respectively, 1.13, 3.74, 4.18, 3.64, 2.81, and 2.00 times more toxic to HepG2 and 2.06, 1.58, 1.76, 2.54, 1.40, and 2.69 times more toxic to MCF‐7 breast cancer cells than in normal Vero cells.