Phenolic furanochromene hydrazone derivatives: Synthesis, antioxidant activity, ferroptosis inhibition, DNA cleavage and DNA molecular docking studies.

ABSTRACT

Twenty-four phenolic furanochromene hydrazone derivatives were designed and synthesized in order to evaluate structure-activity relationships in a series of antioxidant-related assays. The derivatives have varying substitution patterns on the phenol ring, with some compounds having one, two or three hydroxy groups, and others containing one hydroxy group in combination with methoxy, methyl, bromo, iodo and/or nitro groups. Antioxidant activity was determined using the DPPH free radical scavenging and CUPRAC assays. Compounds containing ortho-dihydroxy and para-dihydroxy patterns had the highest free radical scavenging activity, with IC50 values ranging from 5.0 to 28 µM. Similarly, derivatives with ortho-dihydroxy and para-dihydroxy patterns, together with a 4-hydroxy-3,5­dimethoxy pattern, displayed strong copper (II) ion reducing capacity, using Trolox as a standard. Trolox equivalent antioxidant capacity (TEAC) coefficients for these derivatives ranged from 1.75 to 3.97. As further evidence of antioxidant potential, greater than half of the derivatives reversed erastin-induced ferroptosis in HaCaT cells. In addition, twenty-three of the derivatives were effective at cleaving supercoiled plasmid DNA in the presence of copper (II) ions at 1 mM, with the 3,4­dihydroxy derivative showing cleavage to both the linear and open circular forms at 3.9 uM. The interaction of the phenolic furanochromene derivatives with DNA was confirmed by molecular docking studies, which revealed that all the derivatives bind favorably in the minor groove of DNA.