SÍNTESE DE DERIVADOS DA HIPAFORINA E AVALIAÇÃO DA ATIVIDADE INIBITÓRIA SOBRE ACETILCOLINESTERASE

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease, considered the most common dementia worldwide. AD leads to a deficiency of neurotransmitters, mainly acetylcholine (ACh), one of those responsible for the transmission of nervous stimuli. Although AD has no cure, treatment using acetylcholinesterase enzyme inhibitors (AChEis) is the most used. There are currently 3 drugs approved by the Food and Drug Administration that act as AChEis and are used for the treatment of AD, but due to low bioavailability and toxicity problems, the search for new promising structures has still been relevant, so much so that in 2021 more than 1600 articles on AD were published. In a recent study, we performed the synthesis of L and D-hypaphorine and tested the potential as AChEis, L-hypaphorine proved to be a specific inhibitor of AChE, acting only in the cerebellum region, whereas D-hypaphorine acted by inhibiting the enzyme in four brain regions (cerebellum, striatum, hippocampus and cortex). In this context, this work proposes to synthesize hypaphorine derivatives in order to improve their anticholinesterase potential. In our study, the synthetic strategies and routes addressed for the synthesis of three different series of hypaphorine analogues were presented, as well as the presentation of the biological evaluation of the synthesized compounds. The first series aims to synthesize 2 new enantiomers, evaluating the influence of the increase in the carbonic chain between the amine and the carbonyl. The second will deal with the synthesis of 9 unpublished analogues of these compounds with different substituted benzene rings linked to carbonyl. And in the third, the synthesis of 8 hypaphorine analogs with different esters and amine-linked groups will be discussed. To analyze the anticholinesterase potential of the synthesized compounds, the Ellman method was used. The synthesis of series 1 compounds was not successful, due to the non-formation of intermediates 10a and 10b. The indole chalcones (series 2) were obtained with good yields after reaction optimization and they showed promising results in AChE inhibitory activity in which compounds 15b and 15g showed IC50 of 273.2 and 230.1 μM respectively. Compounds 19, 20 and 21 of series 3 were obtained with moderate yields, with only ethyl and butyl esters being the most active in the AChE inhibition assay at a concentration of 500 μM.