Design, Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel Naphthoquinone‐Triazole Hybrids as Potential FGFR1 Tyrosine Kinase Inhibitors

Abstract A new series of 1,4‐naphthoquinone‐triazole derivatives 5 – 21 were synthesized using nucleophilic substitution and CuAAC reactions. The compounds were investigated for their cytotoxic activities against four cancer cell lines (i. e., HuCCA‐1, T47D, MOLT‐3, and HepG2) as well as a normal cell line (Vero). Most of the compounds showed active cytotoxic effects on all tested cancer cells without cytotoxicity to the normal cells. Particularly, compound 20 showed promising activity against the T47D with comparable effect to that of the known drug, doxorubicin. Compounds 16 and 21 exhibited the greatest FGFR1 inhibitory potency with nanomolar IC 50 values of 1.31±0.51 and 3.17±0.33 nM, respectively. Interestingly, the derivative 16 showed comparable inhibitory potency with the known FGFR1 inhibitor, AZD4547. Molecular docking and molecular dynamics simulations were conducted and revealed that both compounds could occupy within the ATP‐binding pocket of the target FGFR1 and shared common interacting key amino acids residues (i. e., Leu484, Val492, and Leu630) with those of inhibitor, AZD4547. The simulations also suggested that the naphthoquinone‐triazole skeleton was found to be a promising structural characteristic essential for effective inhibition of FGFR1. Additionally, the drug‐likeness prediction displayed that these compounds ( 16 and 21 ) are drug‐like molecules with possibility for further development.