Molecular modeling and antioxidant activity of newly synthesized 3‑hydroxy-2-substituted-thiophene derivatives

Abstract

A facile synthesis of 3‑hydroxy-4-(4-hydroxyphenylazo)thiophenes with various functional groups at position-2 of thiophene ring and their corresponding O-acetylated products is described. The synthetic strategy is based on cyclization of the precursor ethyl 2-(2-(4-hydroxyphenyl)hydrazono)-3-(phenylamino)-3-thioxopropanoate with the appropriate α-chlorinated reagents (namely; chloroacetone, phenacyl chloride, ethyl chloroacetate and chloroacetonitrile). The produced 3‑hydroxy-4-(4-hydroxyphenylazo)thiophenes were acetylated upon heating in acetic anhydride to yield the corresponding 3‑hydroxy-4-(4-acetoxyphenylazo)thiophenes and/or 3-acetoxy-4-(4-acetoxyphenylazo)thiophenes. The synthesized thiophene derivatives were characterized by IR, 1H NMR and mass spectroscopic analyses. The DFT modeling of the synthesized derivatives offered a reasonable description about why the acetylation reaction was occurred on the phenolic OH group rather than the OH group at position-3 of thiophene ring. While in case of 2-cyano-3‑hydroxy-4-(4-hydroxyphenylazo)-5-(phenylamino)-thiophene, both hydroxyl groups were acetylated. The antioxidant activities for the synthesized compounds were assessed through DPPH technique. The 3-hydroxythiophene derivatives 5a-c displayed significant activity with IC50 values (3.01–26.27 µg/mL) using BHA, BHT and ascorbic acid as reference antioxidants. Meanwhile, the results of molecular docking study that applied on the synthesized thiophene derivatives supported the experimental antioxidant assay.