Síntese e avaliação farmacológica de novos derivados cumarínicos híbridos planejados como protótipos de teranósticos para a doença de Alzheimer

Abstract

Alzheimer's disease (AD) is a very common neurodegenerative disease and is considered the most common form of dementia. Data from ONU indicate that due to the expected increase in the life expectancy of the world's population, the increase in the number of people with dementia will increase, reaching 82 million in 2030 and 152 million in 2050, so AD is considered a major public health problem. The Knowledge of disorders has led to development of drugs with symptomatic effects, cholinesterase inhibitors, approved in many countries. However, these drugs only act in the behavioral state and research advances in the pathogenesis of AD have also led to potential disease-modifying prototypes, such as metal complexers, which are in the clinical phase. Another increasing approach to AD is the theranostics compounds, which combine therapeutic and diagnostic properties, presenting in a single agent, in order to optimize the efficacy of drug therapy. Within the universe of compounds that can act as sensors for diagnosis, coumarins proved to be an excellent prototype of theranostic due to the luminescence properties and the large number of pharmacological activities. In this context, the objective of this work was to design hybrid fluorescence coumarins, which has potential application as theranostic for AD through the inhibition of AChE and complexation to metals. Two series of coumarins were synthesized and characterized. The first series of compounds (CCM), aiming the evaluation of the fluorescence and complexation properties of the coumarins proposed, was synthesized by two different synthetic protocols: conventional heating and by microwave irradiation, which increased the yields and the reduction of 23h in reaction time. Five compounds were selected and their photophysical characterization in methanol and water was performed, showing different behaviors according to the polarity of the medium. Additionally, as planned, some coumarins showed the ability to act as Zn2+ probe, and one of them, coumarin-semicarbazone, proved to be useful as fluorescence probe also in aqueous medium. The second series (HM), planned with the hybridization between the pharmacophore for inhibition AChE (piperidine) and complexation to Zn2+ (semicarbazide) was synthesized in 4 reaction steps, demonstrating excellent values of inhibitory activity (12.94nM-128.28nM), closed to the available drug donepezil (6.55nM). One Hybrid was further evaluated for the ability to complex Zn2+ in H2O/MeOH, validating the proposal of this work to produce molecular hybrids that could act as theranostic for AD