Avaliação in vitro e in vivo de 2-(4-(metiltio(metilsulfonil))fenil)-3-substituído tiazolidin-4-onas como agentes multialvo para a doença de Alzheimer: uma nova abordagem terapêutica

Abstract

Incidence of dementia increases with age and leads to a decline in cognitive functions and memory. The most common cause of dementia is a progressive neurodegenerative Alz- heimer's disease (AD). The pathophysiology is complex and its exact etiology is still un- clear, but it is known the involvement of the cholinergic system in the development of characteristic symptoms of AD. Currently, few therapeutic options are available and these do not prevent disease progression, causing only symptom relief. These drugs have sig- nificant side effects and are more effective in early stages, losing effectiveness in more advanced stages of the disease. Due to the complexity and the few therapeutic options for the management of patients, this research aimed to evaluate the effect of different 1,3- thiazolidin-4-ones derived from 4-(methylthio)benzaldehyde and 4-(methylsulfonyl)ben- zaldehyde in experimental in vitro studies on the acetylcholinesterase (AChE) activity and through in vivo amnesia model induced by scolopamine. The potential of compounds to inhibit AChE was evaluated in cerebral cortex, hippocampus, and lymphocytes of rats, as well as the binding potential, the three-dimensional fit and the type of inhibition gen- erated from the interaction with the enzyme. This screening stimulated further studies by our research group, to deepen knowledge and describe the potential effects of thiazoli- dinones. Three of tested compounds stood out in IC50 values for AChE inhibition in rat brain: 1b (13.81 μM and 3.13 μM in cerebral cortex and hippocampus, respectively), 1c (55.36 μM and 44.33 μM) and 2b (3.11 μM in both structures). These compounds were also able to inhibit AChE in lymphocytes. The results revealed that the substituent derived from N-(3-aminopropyl)piperidine (b) demonstrated important for AChE inhibition. Mo- lecular docking revealed a three-dimensional fit like donepezil and ACh, and studies of enzymatic kinetics demonstrated a mixed inhibition type for these three compounds. Due to the fact of compound 1b was capable to inhibit both G1 and G4 AChE isoforms, it was selected for the sequence of in vivo trails. Therefore, 2-(4-(methylthio)phenyl)-3-(3-(pi- peridin-1-yl)propyl)thiazolidin-4-one (encoded DS12) has been taken into further studies to assess its preventive effect against to scopolamine-induced memory deficit model. 7- day pretreatment with DS12 (5 or 10 mg/kg) proved to be able to prevent the memory decline caused by scopolamine (1 mg/kg), through inhibitory avoidance test, and to pre- vent neurochemical changes caused by scopolamine: increased levels of reactive species, such as ROS; reduced activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD); increased AChE activity in cerebral cortex, hippocampus and lympho- cytes, and of BuChE activity in serum; and reduction of Na+/K+-ATPase activity. There- fore, it is noteworthy that DS12 prevented the effects of scopolamine without demonstrat- ing changes in hepatic and renal markers. Thus, DS12 emerges as a multi-target com- pound to prevent neurobio-chemical changes in experimental models of AD.