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Photochemical synthesis and functionalization of benzobicyclo[3.2.1]octadienes as potential cholinesterase inhibitors

A continuous flow-photochemistry setup was evaluated with the aim to enable a more efficient protocol for the synthesis of benzobicyclo[3.2.l]octadiene skeleton by intramolecular [2+2]-photocycloaddition reaction. This was the first application of the flow-photochemistry on β-heteroaryl-o-divinylbenzenes and o-vinylphenyl substituted butadienes. Numerous compounds with the bicyclo[3.2.l]-skeleton are proven as potent inhibitors of dopamine and serotonin transporters and also play a crucial role in the treatment of central nervous system and Alzheimer’s disorders. Some of the previously prepared photoproducts showed good cholinesterase inhibition activity, but the main disdvantages were high lipophilicity values and low solubility. Further functionalization of photoproducts was explored in order to achieve better ADME properties. New amines were synthesised using amination reaction, while the addition to the isolated double bond resulted in new epoxides, alcohols and ethers. The furan ring as part of benzobicyclo[3.2.1]-core was suitable substrate for the synthesis of new oximes and oxime ethers and acyl derivatives. Photochemical and especially photophysical behavior of the butadiene derivatives where p- fluorophenyl, p-dimethylaminophenyl, and p- nitrophenyl rings were incorporated into mono- or di-arylbutadiene analogues were investigated and explored. Triazole moiety is important structural part of biologically active compounds and their photochemical reactivity can be different from the corresponding compounds with the phenyl ring. In continuation of the work the investigation was extended by introduction of the triazole ring into the o-divinylbenzene moiety.

ADME properties ; benzobicyclo[3.2.1]octadienes ; cholinesterase ; continuous-flow photochemistry ; functionalized polycyclic skeleton ; physico-chemical properties

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