Derivados adamantoides multialvos para a terapia da doença de Alzheimer: testes in vitro e in vivo em modelos animais não convencionais

Abstract

Alzheimer's disease (AD) is characterized by the deposition of β-amyloid plaques and the formation of neurofibrillary tangles of tau protein. Currently, in Brazil, only five drugs are available for its treatment: donepezil, rivastigmine, galantamine (acetylcholinesterase inhibitors - AChE), memantine (an N-methyl-D-aspartate receptor antagonist - NMDA), and donanemab (an antiamyloidogenic monoclonal antibody). These treatments are unable to prevent neuronal loss, temporarily avoiding the progression of the symptoms, making the search for more effective compounds a priority. To contribute to this goal, the present work aimed to synthesize and characterize seven adamantoid-aminated compounds with a hybrid molecular structure that could interact with AChE and NMDAr. The synthesis of the organic compounds was carried out in two steps: replacement of the hydroxyl group of adamantane-1-methanol with iodine, followed by replacement of the iodine with the amino group. Characterization was performed by nuclear magnetic resonance (NMR) and infrared vibrational spectroscopy (IR). The compounds were evaluated in vitro for AChE inhibition capacity (Ellman test) and antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH). Cytogenotoxicity was assessed by the Allium cepa test and acute toxicity by the Artemia salina assay. Cytotoxicity was determined in glial cells (U87) and mouse fibroblasts (L929) by the MTT test. The most promising compound, N 1 -(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1,4-butanediamine dihydrochloride (AG03), was evaluated in vivo for neurological activity using different C. elegans strains. The results indicated that the proposed synthetic route was technically feasible, allowing the obtain pure compounds in good yields (50 to 85%). In vitro, they had high AChE inhibition capacity (78 to 97%), but low antioxidant activity (less than 35%). The samples had different cytotoxic effects against the cells used. Among the synthesized molecules, AG03 demonstrated the greatest enzyme inhibition capacity (97% AChE), was not cytogenotoxic (at a concentration of 0.06 mg/L), and was not toxic to the larvae of the microcrustacean Artemia salina. Ultimately, the compounds exhibit high AChE inhibition, and AG03 shows a multitarget effect, modulating cholinergic and glutamatergic responses in in vivo assays. Therefore, this work represents a relevant contribution to research on AD's treatments.