Antiproliferative evaluations of triazoloquinazolines as classical DNA intercalators: Design, synthesis, ADMET profile, and molecular docking

Abstract

Novel triazoloquinazolines were designed and synthesized and evaluated as anticancer agents against HepG2 and HCT-116 cells. The biological testing data corresponded well to those of the molecular docking studies. The HCT-116 cell line was most affected due to the actions of our derivatives. Derivative 7_a was the most potent one against both HepG2 and HCT116 cells, with IC₅₀ = 7.98 and 5.57 µM, respectively. This compound showed anticancer activity that was nearly equipotent to that of doxorubicin against HepG2 cells, but higher than that of doxorubicin against HCT116 cells (IC₅₀ = 7.94 and 8.07 µM, respectively). Compounds 8, 7_b , and 6_f showed excellent anticancer activities against both the HCT116 and HepG2 cell lines. The highly active compounds 6_f , 7_a , 7_b , and 8 were evaluated for their DNA-binding activities. Compounds 7_a and 8 showed the highest binding activities. These derivatives potently intercalate in DNA, at IC₅₀ values of 42.90 and 48.13 µM, respectively. Derivatives 6_f and 7_b showed good DNA-binding activities, with IC₅₀ values of 54.24 and 50.56 µM, respectively. Furthermore, in silico calculated ADMET profiles were established for our four highly active derivatives, in comparison to doxorubicin. Our derivatives 6_f , 7_a , 7_b , and 8 showed a very good ADMET profile. Compounds 6_f , 7_a , 7_b , and 8 follow Lipinski's rules, while doxorubicin violates three of these rules.