[1,2,4]Triazolo[4,3-a]quinoxaline and [1,2,4]triazolo[4,3-a]quinoxaline-1-thiol-derived DNA intercalators: design, synthesis, molecular docking, in silico ADMET profiles and anti-proliferative evaluations

Abstract

In view of their DNA intercalation activities as anticancer agents, 17 novel [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized and evaluated against HepG2, HCT-116 and MCF-7 cells. Molecular docking studies were performed to investigate the binding modes of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with those obtained from the molecular modeling studies. MCF-7 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compound 12_d was found to be the most potent derivative of all the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines, with IC₅₀ = 22.08 ± 2.1, 27.13 ± 2.2 and 17.12 ± 1.5 μM, respectively. Although this compound displayed nearly one third of the activity of doxorubicin (IC₅₀ = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 μM, respectively), it may be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. Compounds 12_a, 10_c and 10_d displayed very good anticancer activities against the three HepG2, HCT116 and MCF-7 cancer cell lines, with IC₅₀ = 31.40 ± 2.8, 28.81 ± 2.4 and 19.72 ± 1.5 μM for 12_a, 33.41 ± 2.9, 29.96 ± 2.5 and 24.78 ± 1.9 μM for 10_c, and 37.55 ± 3.3, 30.22 ± 2.6 and 25.53 ± 2.0 μM for 10_d. The most active derivatives, 10_c, 10_d, 10_h, 12_a, 12_b and 12_d, were evaluated for their DNA binding activities. Compound 12_d displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC₅₀ value (35.33 ± 1.8 μM), which is nearly equipotent to that of doxorubicin (31.27 ± 1.8 μM). Compounds 12_a and 10_c exhibited good DNA-binding affinities, with IC₅₀ values of 39.35 ± 3.9 and 42.35 ± 3.9 μM, respectively. Finally, compounds 10_d, 10_h and 12_b showed moderate DNA-binding affinities, with IC₅₀ values of 50.35 ± 3.9, 57.08 ± 3.3 and 59.35 ± 3.2 μM, respectively.