Arylureidoaurones: Synthesis, in vitro α-glucosidase, and α-amylase inhibition activity

Abstract

Because of the colossal global burden of diabetes, there is an urgent need for more effective and safer drugs. We designed and synthesized a new series of aurone derivatives possessing phenylureido or bis-phenylureido moieties as α-glucosidase and α-amylase inhibitors. Most of the synthesized phenylureidoaurones have demonstrated superior inhibition activities (IC₅₀s of 9.6-339.9 μM) against α-glucosidase relative to acarbose (IC₅₀ = 750.0 μM) as the reference drug. Substitution of aurone analogues with two phenylureido substituents at the 5-position of the benzofuranone moiety and the 3' or 4' positions of the 2-phenyl ring resulted in compounds with almost 120-180 times more potent inhibitory activities than acarbose. The aurone analogue possessing two phenylureido substitutions at 5 and 4' positions (13) showed the highest inhibition activity with an IC₅₀ of 4.2 ± 0.1 μM. Kinetic studies suggested their inhibition mode to be competitive. We also investigated the binding mode of the most potent compounds using the consensually docked 4D-QSAR methodology. Furthermore, these analogues showed weak-to-moderate non-competitive inhibitory activity against α-amylase. 5-Methyl substituted aurone with 4'-phenylureido moiety (6e) demonstrated the highest inhibition activity on α-amylase with an IC₅₀ of 142.0 ± 1.6 μM relative to acarbose (IC₅₀ = 108 ± 1.2 μM). Our computational studies suggested that these analogues interact with a hydrophilic allosteric site in α-amylase, located far from the enzyme active site at the N-terminal.