Abstract

With the increasing realization that modulating a multiplicity of targets can be an asset in the treatment of multifactorial disorders, we hereby report the synthesis and evaluation of the first compounds in which antioxidant, anti-inflammatory as well as squalene synthase (SQS) inhibitory activities are combined by design, in a series of simple molecules, extending their potential range of activities against the multifactorial disease of atherosclerosis.

The activity of the initially synthesized antihyperlipidemic morpholine derivatives was evaluated in vitro and in vivo. We further compared the in vitro SQS inhibitory action of these derivatives with theoretically derived molecular interactions by performing an in silico docking study. Based on low energy preferred binding modes, we designed potentially more potent SQS ligands. We proceeded with synthesizing and evaluating these new structures to show that the new derivatives were significantly more active than formerly developed congeners, both as SQS inhibitors (20–70-fold increase in activity) and antioxidants (4–30-fold increase in activity). A significant correlation between experimental activity and the corresponding binding free energy of the docked compounds was shown.

These results, taken together, show a promising alternative and novel approach for the design and development of multifunctional antiatherosclerosis agents.