Microwave synthesis, X-ray analysis, in vitro and in silico evaluation of the antioxidant and anti-urease activities of novel acridines derived from β-enaminones

Abstract

A series of 14 acridine derivatives was synthesized from the condensation of different β-enaminones and aromatic aldehydes, under microwave irradiation in catalyst-free conditions. The synthesis was favored for its rapidity, good yields, and environmental friendliness as it avoided the use of dangerous products and involved the employment of simple reactants and benign reaction conditions. The introduction of an ortho substituent in the aromatic aldehyde ring led to novel acridine-derived molecules containing hydroxyl groups. The structure of imino-acridine 5d was fully determined using XRD method and confirmed the obtainment of both E-(R) and E-(S) isomers. In vitro studies were performed to evaluate the antioxidant capacity of the synthesized compounds as well as the anti-urease activity. The results showed that the novel hydroxylated compound 5m was potent in the DPPH antioxidant test (IC₅₀ = 0.99 ± ¦0.13 µmol/mL) and gave an interesting activity against urease enzyme with an IC₅₀ of 0.03 ± ¦0.01 µmol/mL that is considered better than the standard molecule thiourea (IC₅₀ = 0.10 ± ¦0.004 µmol/mL). An in silico investigation that consisted of a molecular docking study and molecular dynamics simulation was completed to predict the binding mode of the novel hydroxylated compound 5m towards active sites of both xanthine oxidase and urease enzymes as antioxidant and anti-urease targets, respectively. Furthermore, we employed DFT calculations to analyze the electronic and geometric properties of the optimal compound, 5m The HOMO and LUMO band gap energies, as well as the molecular electrostatic potential surface, were deduced for the stable structure.