Arylureidoaurones: Synthesis, in vitro α-glucosidase, and α-amylase inhibition activity
Mohammad Kazempour-Dizaji, Somayeh Mojtabavi, Arash Sadri, Araz Ghanbarpour, Mohammad Ali Faramarzi, Latifeh Navidpour
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 (IC 50 s of 9.6–339.9 μM) against α-glucosidase relative to acarbose (IC 50 = 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 IC 50 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 IC 50 of 142.0 ± 1.6 μM relative to acarbose (IC 50 = 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.