Síntese e avaliação farmacológica de novos ligantes multialvo visando ao tratamento de doenças neurodegenerativas

Abstract

The term "neurodegenerative disease" includes a range of diseases that primarily affect the neurons of the human brain, major components of the central nervous system, when they are damaged generate a set of progressive neurological injury, leading to problems with locomotion, dementia, memory loss, neuronal death etc. The main neurodegenerative diseases (NDs) are Alzheimer, Parkinson and Huntington. The pharmacological treatments aimed to treat the characteristic symptoms of each disease, but the treatment is inefficient due to the multi-factorial character that includes oxidative stress, neuroinflammation and proteotoxicity. In this context, the development of a treatment that covers all factors involved in NDs is a medical and socioeconomic priority. This study aimed at the rational design, synthesis, characterization and pharmacological evaluation of three series of new compounds inspired by the properties of donepezil (1), curcumin (2) and thalidomide (3). These series are molecular hybrids from standard compounds joined by a hydrazide spacer or an amide. 36 substances were synthesized, of which 4 compounds were cholinesterase inhibitors: PQM-189, PQM-263 and PQM-266, selective AChE inhibitors (IC50 of 3.15, 13.04 and 9.19 μM, respectively) and PQM-272, selective BuChE inhibitor (IC50 of 11.94 μM). The ligands PQM-225, PQM-263 and PQM-265 and PQM-266 had a significant antioxidant profile against DPPH, t-BOOH and 6-OHDA-induced oxidative stress, especially PQM-263 which induced about 31% release of intracellular glutathione at a concentration of 20 μM. In addition, PQM-225 inhibited 53% of MAO B enzymatic activity. Finally, PQM-189 exhibited anti-inflammatory potential by regulating LPS treatment through down-regulation of iNOS and IL-1β gene expression. Therefore, the neuroprotective character of these compounds in the elimination of free radicals due to oxidative stress and inflammatory processes is emphasized.