Synthetic Impatienol analogues as potential cyclooxygenase-۲ inhibitors: a preliminary study

Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation ofprostanoids, including prostaglandins, prostacyclin and thromboxane, which are mediatorsof inflammation. COX-۲, undetectablein normal tissues, and induced during inflammation,hypoxia and Wnt-signalling, is present in many cancers. A series of dimeric ۲-hydroxy-۱, ۴-naphthoquinone analogues was designed and subsequently synthesized via single step conversion of readily available aromatic aldehydes. All compoundswere evaluated by cyclooxygenase-۲ (COX-۲) assays in vitro by surface plasmon resonance(SPR) to determine inhibitorypotency. Compounds ۱-۱۰ showed moderate to good inhibition with Kd values ranging from ۱.۲۵x۱۰-۶M to ۱.۹۷x۱۰-۱۰M for COX-۲. Diclofenac and nimesulide were taken as standard drugs to compare the results of SPR assay.Mode of binding of most potent compound ۱۰ (Kd=۱.۹۷x۱۰-۱۰M) was further investigatedby molecular docking studies. Multiple receptor conformations (MRC) of the binding site were generated to simulate the probable protein movement. The ensemble docking studies were carried out to analyze various interactions that lead to the binding.

Keywords:

Cyclooxygenase-۲ , Impatienol , Naphthoquinone , Molecular docking , Multiple receptor conformations