Design, Synthesis, and Biological Evaluation of Anthracene Derivatives as Potent Antioxidants: Experimental, DFT , and Docking Studies

Abstract

ABSTRACT A series of 10 anthracene derivatives ( MM‐1‐MM‐10 ), comprising anthracene cyanoacrylamides ( MM‐1‐MM‐5 ) and anthracene hydrazinyl‐thiazoles ( MM‐6‐MM‐10 ), was synthesized from anthracene‐9‐carbaldehyde and characterized by FT‐IR, 1 H NMR, 13 C NMR, mass spectrometry, and elemental analysis. The two‐family design was used to test whether replacing the cyanoacrylamide linker with a hydrogen‐donating hydrazinyl‐thiazole unit improves radical‐scavenging behavior while retaining the extended anthracene pi‐system. Antioxidant activity was evaluated by the DPPH assay using ascorbic acid as the reference. MM‐10 and MM‐9 were the most active compounds, with IC 50 values of 0.0033 ± 0.0002 and 0.0053 ± 0.0003 mg/mL, respectively, compared with 0.0164 ± 0.0006 mg/mL for ascorbic acid. MM‐7 and MM‐6 also showed strong activity, with IC 50 values of 0.0123 ± 0.0006 and 0.0162 ± 0.0006 mg/mL, respectively. Gas‐phase DFT calculations were performed at the B3LYP/6‐311G(d, p) level. An exploratory descriptor‐activity analysis across the 10 compounds indicated that donor‐related descriptors, particularly the nucleophilicity index (Nu), were more closely associated with DPPH potency than the HOMO‐LUMO gap considered alone. Because the data set is small, this correlation is interpreted as hypothesis‐generating rather than as a generally predictive model. Docking against the KEAP1 Kelch domain (PDB ID: 8IVR) suggested favorable binding poses for MM‐3 , MM‐7 , MM‐9 , and MM‐10 relative to the co‐crystallized inhibitor. These docking results provide supportive mechanistic hypotheses at the pathway level but do not establish cellular KEAP1 inhibition or biological antioxidant activity. Overall, the experimental data identify the hydrazinyl‐thiazole subseries, particularly MM‐7 , MM‐9 , and MM‐10 , as promising scaffolds for further cellular, toxicity, and in vivo evaluation.