Synthesis and Evaluation of 2′-Hydroxyethyl trans-Apovincaminate Derivatives as Antioxidant and Cognitive Enhancer Agents

A series of trans-2′-hydroxyethyl and 2′-acyloxyethyl apovincaminates 4b−f and 7b−f has been synthesized and evaluated for their antioxidant and antiamnesic effects. The new esters were prepared from 4a and 7a ethyl esters or from the corresponding carboxylic acid sodium salt. For starting materials 11a,b, a new stereoselective trans-reduction was elaborated. From the combined results of the data obtained from in vitro and in vivo tests and examination of the metabolism, (3R,16S)-2′-hydroxyethyl apovincaminate (7b, RGH-10885) was identified as the most promising compound, owing to its potent neuroprotective and antiamnesic activities. The in vivo effectiveness of selected compounds on the cognitive functions was studied in a one-trial passive avoidance task and a water-labyrinth test.