Diverse synthetic approaches to 3-arylmethylidene- and bis-3,5-arylmethylidene-N-benzylpiperidin-4-ones with thiophene scaffolds: The comparative experimental study

Abstract

As one of the most active compounds, the mono-substituted 3-arylmethylidene-N-benzylpiperidin-4-ones were found to possess similar acetylcholinesterase (AChE) inhibitory activity as the drug donepezil. Nevertheless, since their discovery, their investigation in pharmaceutical sciences remains undeveloped, probably because of their synthetic unavailability. On the other hand, their bis-substituted analogues – chalcones/dienones - exhibit structural similarity to curcumin and their preparation represents an easy and well-known process. Accordingly, our research efforts are concerned with investigations of synthetic approaches towards the N-benzylpiperidon-4-one-based monoenoes 4a-6a in comparison with the synthesis of their bis-substituted counterparts 4b-6b. Both, either the synthesis of monosubstituted derivatives or bis-substituted chalcones are with importance in drug design. The substitution pattern of N-benzylpiperidin-4-one was realized through the thiophene- and [2,2´]bithiophene-scaffolds. Since spatial arrangement is crucial for the pharmacological effect, geometry optimizations are included.