Triazoloquinoxalines-based DNA intercalators-Topo II inhibitors: design, synthesis, docking, ADMET and anti-proliferative evaluations

Abstract

Sixteen [1, 2, 4]triazolo[4,3-a]quinoxalines as DNA intercalators-Topo II inhibitors have been prepared and their anticancer actions evaluated towards three cancer cell lines. The new compounds affected on high percentage of MCF-7. Derivatives 7e , 7c and 7b exhibited the highest anticancer activities. Their activities were higher than that of doxorubicin. Molecular docking studies showed that the HBA present in the chromophore, the substituted distal phenyl moiety and the extended linkers enable our derivatives to act as DNA binders. Also, the pyrazoline moiety formed six H-bonds and improved affinities with DNA active site. Finally, 7e , 7c and 7b exhibited the highest DNA affinities and act as traditional intercalators of DNA. The most active derivatives 7e , 7c, 7b, 7g and 6e were subjected to evaluate their Topo II inhibition and DNA binding actions. Derivative 7e exhibited the highest binding affinity. It intercalates DNA at IC 50 = 29.06 µM. Moreover, compound 7e potently intercalates DNA at an IC 50 value of 31.24 µM. Finally, compound 7e demonstrated the most potent Topo II inhibitor at a value of 0.890 µM. Compound 7c exhibited an equipotent IC 50 value (0.940 µM) to that of doxorubicin. Furthermore, derivatives 7b, 7c, 7e and 7g displayed a high ADMET profile.

New [1,2,4]triazolo[4,3‐c]quinazoline derivatives as vascular endothelial growth factor receptor‐2 inhibitors and apoptosis inducers: Design, synthesis, docking, and antiproliferative evaluation

“…The toxicity parameters of the synthesized compounds were calculated using Discovery Sstudio 4.0 as described in the Supporting Information. [ 82 ]…”

[1,2,4]triazolo[4,3-a]quinoxaline as Novel Scaffold in the Imiqualines Family: Candidates with Cytotoxic Activities on Melanoma Cell Lines

“…Non-C1 methylated derivatives were also synthetized, and the more potent compounds were tested as topoisomerase II inhibitors [43]. They also recently highlighted chalcones and their pyrazole derivatives as potent MCF-7 antiproliferative agents with DNA-binding and topoisomerase II inhibition activities [44]. Via a hybrid pharmacophore approach, Kaneko et al presented C1-and C4-substituted- [1,2,4]triazolo [4,3-a]quinoxaline based on Imiquimod and EAPB0203 [45][46][47].…”

“…To our knowledge, there is no published review on general synthetic pathways of the [1,2,4]triazolo [4,3-a]quinoxaline scaffold, but numerous approaches have been reported to prepare specific compounds (Scheme 1). Even if the intermediate 2,3-dichloroquinoxaline is commercially available, it is also possible to prepare this intermediate by the chlorination of 2,3-dihydroxyquinoxaline carried out by thionyl chloride, which is obtained from 1,2-diaminobenzene condensed with oxalic acid in a 4N hydrochloric acid solution [41,42,44]. Some strategies have been described to build promising tri-heterocyclic compounds from 2-hydrazinoquinoxalines obtained by substituting one of the two chlorines of 2,3-dichloroquinoxaline by hydrazine hydrate.…”

“…Nevertheless, the limited diversity of this kind of reagents does not allow for the preparation of a heterocyclic compounds bank diversely substituted in position 1 as we envisaged. Carboxylic acids have been used to form the tri-heterocycle but this strategy is relatively less described (Route B, Even if the intermediate 2,3-dichloroquinoxaline is commercially available, it is also possible to prepare this intermediate by the chlorination of 2,3-dihydroxyquinoxaline carried out by thionyl chloride, which is obtained from 1,2-diaminobenzene condensed with oxalic acid in a 4N hydrochloric acid solution [41,42,44]. Some strategies have been described to build promising tri-heterocyclic compounds from 2-hydrazinoquinoxalines obtained by substituting one of the two chlorines of 2,3-dichloroquinoxaline by hydrazine hydrate.…”