Synthesis and cholinesterase inhibition of cativic acid derivatives

NATALIA P. ALZA; VICTORIA RICHMOND; CARLOS J. BAIER; ELEONORA FREIRE; RICARDO BAGGIO; ANA PAULA MURRAY

BIOORGANIC & MEDICINAL CHEMISTRY.

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2014 vol. 22 p. 3838 - 3849

0968-0896

Alzheimer?s disease (AD) is a neurodegenerative disorder associated with memory impairment and cognitivedeficit. Most of the drugs currently available for the treatment of AD are acetylcholinesterase(AChE) inhibitors. In a preliminary study, significant AChE inhibition was observed for the ethanolicextract of Grindelia ventanensis (IC50 = 0.79 mg/mL). This result prompted us to isolate the active constituent,a normal labdane diterpenoid identified as 17-hydroxycativic acid (1), through a bioassay guidedfractionation. Taking into account that 1 showed moderate inhibition of AChE (IC50 = 21.1 lM), selectivityover butyrylcholinesterase (BChE) (IC50 = 171.1 lM) and that it was easily obtained from the plant extractin a very good yield (0.15% w/w), we decided to prepare semisynthetic derivatives of this natural diterpenoidthrough simple structural modifications. A set of twenty new cativic acid derivatives (3?6) was preparedfrom 1 through transformations on the carboxylic group at C-15, introducing a C2?C6 linker and atertiary amine group. They were tested for their inhibitory activity against AChE and BChE and somestructure?activity relationships were outlined. The most active derivative was compound 3c, with anIC50 value of 3.2 lM for AChE. Enzyme kinetic studies and docking modeling revealed that this inhibitortargeted both the catalytic active site and the peripheral anionic site of this enzyme. Furthermore, 3cshowed significant inhibition of AChE activity in SH-SY5Y human neuroblastoma cells, and was noncytotoxic.