Synthesis, biological and computational studies of flavonoid acetamide derivatives

Abstract

This study reports the synthesis and characterization of a novel class of flavonoid acetamide derivatives (FA) of quercetin, apigenin, fisetin, kaempferol, and luteolin. Flavonoids display numerous biological properties but are limited by aqueous insolubility, enzymatic degradation, instability, and low bioavailability. FAs were synthesized, with 80–82% yields, through the sequential modification of the flavonoid hydroxyl groups into the acetamide moieties. Bioavailability, antioxidant, and ADMET are structure–activity-dependent properties that vary across different classes of flavonoids and dictate the prevalent biological applications of the flavonoids. Thus, the FAs were evaluated for their bioavailability, antioxidant, and ADMET toxicity properties versus the unmodified flavonoids (UFs). In vitro bioavailability analysis shows that the UFs have bio-availabilities in the range of 10.78–19.29% against that of the FAs in the range of 20.70–34.87%. The antioxidant capacity was measured using the 2,2-diphenyl-1-picrylhydrazyl (DPPH·) assay with recorded IC₅₀ values of 2.19–13.03 μM for the UFs. Conversely, the FAs had high DPPH IC₅₀ values ranging from 33.83 to 67.10 μM and corresponding to lower antioxidant activity. The FAs showed favorable ADMET properties. The modification of flavonoids into FAs significantly improves the bioavailability and the ADMET toxicity properties, albeit with decreased antioxidant activity. This work highlights the effect of the global modification of the flavonoids with the acetamide groups on the bioavailability, antioxidant, and ADMET toxicity properties which are critical determinants in the biological applications of the flavonoids.