Synthesis and modeling of oxime derivatives of the furo-benzobicyclo[3.2.1]octadiene obtained by flow-photochemistry

Spojevi iz skupine oksima su od prije poznati kao dobri reaktivatori fosforiliranih kolinesteraza, kao i njihovi inhibitori. Acetilkolinesteraza održava normalnu razinu acetilkolina hidrolizom, a inhibicija ovog enzima posebno je važna kod smanjenja simptoma Alzheimerove bolesti kod koje je razina acetilkolina snižena. Prethodno sintetizirani benzobiciklo[3.2.1]oktadieni pokazali su obećavajuće rezultate biološke aktivnosti te je u ovom radu nastavljena daljnja funkcionalizacija koristeći spoj 1 kao početni reaktant. U cilju dobivanja do sada literaturno nepoznatih oksima i oksimskih etera sintetizirani su, izolirani i spektroskopski okarakterizirani spojevi 2-6a. Prilikom sinteze, osim predviđenih produkata, dobiveni su i srodni derivati u kojima se otvorio furanski prsten bicikličkog kostura na dva različita načina. Odabranim sintetiziranim i nesintetiziranim oksimima i oksimskim eterima u ulozi inhibitora acetil- i butirilkolinesteraze računalno je ispitana relativna termodinamička stabilnost kompleksa enzim-inhibitor s ciljem predviđanja jačine inhibicije. Molekule koje stvaraju stabilnije komplekse trebale bi i eksperimentalno pokazati jaču sposobnost inhibicije kolinesteraza što će se ispitati za sintetizirane spojeve.Oxime derivatives are known from before as good reactivators of phosphylated cholinesterases, as well as their inhibitors. Acetylcholinesterase maintains normal acetylcholine levels by hydrolysis, and inhibition of this enzyme is particularly important in reducing symptoms of Alzheimer's disease in which acetylcholine level is lowered. The previously synthesized benzobicyclo[3.2.1]octadienes showed promising results of biological activity, and further functionalization was continued in this work using compound 1 as the initial reactant. In order to obtain previously unknown oximes and oxime ethers, compounds 2-6a were synthesized, isolated and spectroscopically characterized. During the synthesis, in addition to the products provided, similar derivatives were obtained in which the furan ring of the bicyclic skeleton was opened in two different ways. The selected synthesized and non-synthesized oximes and oxime ethers in the role of acetyl- and butyrylcholinesterase inhibitors were computationally tested for the relative thermodynamic stability of the enzyme-inhibitor complex in order to predict the strength of inhibition. Molecules that form more stable complexes should also experimentally show a stronger ability to inhibit cholinesterases, which will be tested for the synthesized compounds