Cativic acid derivatives as cholinesterase inhibitors

NATALIA P. ALZA; BAIER, CARLOS JAVIER; ANA PAULA MURRAY

Olomouc

Congreso; Trends in Natural Products Research; 2014

Phytochemical Society of Europe, Palacký University Olomouc

Alzheimer´s disease (AD) is a progressive neurodegenerative disorder associated with progressive memory loss, decline of language skills, and other cognitive impairments. AD is pathologically characterized by extracellular deposits of beta-amyloid peptide, neurofibrillary tangles composed by hyperphosphorylated tau-protein, neuronal loss and neurotransmitter dysfunction. The most widely used concept for AD drug development is the cholinergic hypothesis, based on a deficiency of acetylcholine (ACh) in the central nervous system. Acetylcholinesterase (AChE) inhibitors enhance cholinergic neurotransmission trough inhibition of AChE, thus decreasing the breakdown of ACh. Therefore, anti-AChE drugs such as donepezil, rivastigmine, galanthamine and tacrine, were developed for treatment of AD. In a preliminary study a significant AChE inhibition in vitro was observed for a normal labdane diterpene identified as 17-hydroxycativic acid (1), which was isolated from the ethanolic extract of Grindelia ventanensis (Asteraceae) through a bioassay guided fractionation. Taking into account that 1 showed a moderated inhibition of AChE (IC50 = 21.1 µM), selectivity over butyrylcholinesterase (BChE) (IC50 = 171.1 µM) and that it was easily obtained from the plant extract in a very good yield, we decided to prepare a set of twenty derivatives (3-6) of the natural diterpene (1), by connecting the diterpene scaffold with tertiary amine groups through linkers of different chain lengths (scheme 1). This strategy has been successfully applied to the synthesis of AChE inhibitors with flavonoid and coumarin scaffold. AChE and BChE inhibitory activity in vitro of compounds 3-6 was evaluated and compared to that of natural diterpene 1. The IC50 values for cholinesterase inhibition and their selectivity index (SI) for the inhibition of AChE over BChE will be presented. Most of the tested derivatives resulted to be better AChE and BChE inhibitors than 1. The most potent and selective AChE inhibitor resulted to be compound 3c (IC50 = 3.2 µM for AChE), with a four carbon spacer and a pyrrolidine moiety. Furthermore, 3c showed significant inhibition of AChE activity in SH-SY5Y human neuroblastoma cells, with non-cytotoxic effect.