Synthesis, molecular docking, bio-evaluation and quantitative structure activity relationship of new chalcone derivatives as antioxidants

Abstract

The therapeutic suppression of oxidative stress represents an attractive therapeutic target across an array of inflammatory disease setting. The nuclear factor erythroid 2-related factor 2 (Nrf2) and its negative regulator Kelch-like ECH-associated protein1 (Keap1) are principal components in the homeostatic regulatory responses to oxidative and electrophilic stress and as such, reflect promising therapeutic targets. Flavonoids are a structurally diverse class of compounds possessing a wide range of pharmacological properties that have been postulated to suppress inflammation through their suppression of the Nrf2 pathway. The present study describes the synthesis of new 2-Hydroxy-5-nitro chalcones in the flavonoid family by the condensation of acetophenone and benzaldehydes. The structures of these compounds (3a-3e) were elucidated by spectroscopic studies including FTIR, 1H NMR and 13C NMR. Antioxidant potential of the compounds was determined by DPPH and iron chelating assays. Molecular docking analysis revealed that all the compounds had a marked affinity for Keap1 and computational studies revealed that all compounds possessed antioxidant potential. The compounds 3a>3b>3c>3e>3d showed an increasing order in IC50 for iron chelation, but were poor DPPH scavengers. Anti-inflammatory and analgesic activities were determined by carrageenan induced paw edema and acetic acid induced writhing test respectively in Sprague–Dawley rats. Of the compounds studied, both 3a and 3b demonstrated significant anti-inflammatory properties while 3c possessed analgesic effects. These studies suggest that these new 2-Hydroxy-5-nitro chalcones are potential anti-oxidant and anti-inflammatory compounds through their interaction with the Nrf2-Keap1 pathway. Further study of these compounds at the molecular level is now required to validate the presence of Nrf2 dependent anti-inflammatory pathway.