Design, synthesis, acetylcholinesterase inhibition and larvicidal activity of girgensohnine analogs on Aedes aegypti, vector of dengue fever

Girgensohnine alkaloid was used as a natural model in the design and generation of new alkaloid-like alpha-aminonitrile series that was completed by the use of SSA-catalyzed Strecker reaction between commercial and inexpensive substituted benzaldehydes, piperidine (pyrrolidine, morpholine and N-methylpiperazine) and acetone cyanohydrin. Calculated ADMETox parameters of the designed analogs revealed their good pharmacokinetic profiles indicating lipophilic characteristics. In vitro AChE enzyme test showed that obtained alpha-aminonitriles could be considered as AChEIs with micromolar IC50 values ranging from 42.0 to 478.0 mu M (10.3-124.0 mu g/mL). Among this series, the best AChE inhibitor was the Pyrrolidine alpha-aminonitrile 3 (IC50 = 42 mu M) followed by the piperidine alpha-aminonitriles 2 and 6 (IC50 = 45 mu M and IC50 = 51 mu M, respectively), and the compound 7 (IC50 = 51 mu M). In vivo insecticidal activity of more active AChEIs against Aedes aegypti larvae was also performed showing a good larvicidal activity at concentrations less than 140 ppm, highlighting products 2 and 7 that could serve as lead compounds to develop new potent and selective insecticides. (C) 2014 Elsevier Masson SAS. All rights reserved.