Estudos visando à síntese de novos compostos híbridos planejados como inibidores de acetilcolinesterase

Abstract

Alzheimer's disease (AD) is a serious and incurable neuropathology, characterized by a progressive disturbance in memory and other cognitive functions, affecting dramatically the social and occupational behavior. Hitting 37 millions people in the world, AD is considered the main cause of degenerative dementia in individuals over the age 60. With the increase of life expectancy of population worldwide, diseases associated to longevity such as AD and Parkinson's disease perform a big challenge, where the development of more efficient and safety therapeutic agents becomes the main target for research groups and Pharmaceutical Industry. Among the pathophysiological changes associated with the development of AD, the reduction of central cholinergic function has been the main target of the available drugs, which work mainly in the inhibition of acetylcholinesterase, a key enzyme in the biosynthetic cascade and regulation of the concentration of acetylcholine in synaptic clefts. The search for new anti-cholinesterase drugs, with innovative carbon skeleton and pharmacological profile, led us to design a new drug candidate prototype by using molecular hybridization of the structures of donepezil (2) and rivastigmine (3), two drugs available for the AD treatment. Furthermore, we proposed the insertion of an acyl hydrazone subunit aiming to achieve additional anti-inflammatory properties. The synthetic route for the series 26 was based on a convergent approach involving the coupling of the key-intermediates hydrazide 29 and the piperidine aldehyde 33.