Modeling and synthesis of novel oxime derivatives as potential cholinesterase inhibitors

Promising test results on biological activity of our previously described benzobicyclo[3.2.1]octadienes, synthetically obtained by intramolecular photochemical cycloaddition reaction, prompted us to pursue with the further functionalization of this basic skeleton toward oxime derivatives. The free energies of formation of complexes between planned new oximes showing promising ADME properties and the active sites of cholinesterases were calculated using docking and density functional theory, showing that thermodynamical stability of some of the examined complexes is the same as the stability of the complex formed with well known and efficient cholinesterase inhibitor huperzine A. On the basis of calculated stabilities of complexes, the synthesis of several representative new compounds was succesfully performed. In some cases, the furan ring opened on two different ways so different opened oximes and oxime ethers were also formed. All new prepared oximes and oxime ethers present good material for further experimental investigation as inhibitors/reactivators of cholinesterases.