[1,2,4]Triazolo[4,3-c]quinazoline and bis([1,2,4]triazolo)[4,3-a:4',3'-c]quinazoline derived DNA intercalators: Design, synthesis, in silico ADMET profile, molecular docking and anti-proliferative evaluation studies.

In view of their DNA intercalation activities as anticancer agents, novel fifteen [1,2,4]triazolo[4,3-c]quinazoline and bis([1,2,4]triazolo)[4,3-a:4',3'-c]quinazoline derivatives have been designed, synthesized and evaluated against HepG2 and HCT-116. The molecular design was performed to investigate the binding mode of the proposed compounds with DNA active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling studies. HCT-116 was found to be more sensitive cell lines to the influence of the new derivatives. In particular, compounds 16, 18, 11 and 5 were found to be the most potent derivatives with IC = 3.61, 6.72, 7.16 and 5.18 µM respectively against HepG2 cell line. Also, compounds 16, 18, 11 and 5 displayed IC = 2.85, 3.82, 4.97 and 6.40 µM respectively against HCT-116 cell line. These derivatives displayed higher activities than doxorubicin, (IC = 7.94 and 8.07 µM respectively) against the two HepG2 and HCT-116 cell lines. The most active anti-proliferative derivatives 5, 6, 10, 11, 13, 16, 18, 19 and 20 were further evaluated for their DNA-binding affinity which revealed the ability of these compounds to intercalate DNA. The tested compounds displayed very strong to moderate DNA-binding affinities. Compounds 16 and 18 potently intercalate DNA at IC values of 26.03 and 28.37 µM respectively which were lower than IC of Doxorubicin (IC = 31.27). This finding indicated that these derivatives exhibited higher DNA binding activities than Doxorubicin. Also, compounds 11 and 5 displayed very strong DNA binding at IC = 30.84 and 33.56 µM respectively, which were nearly equipotent to that of doxorubicin. Moreover, most of our derivatives exhibited good ADMET profile.