Carreno_2014_Eur.J.Med.Chem_78C_392

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 muM (10.3-124.0 mug/mL). Among this series, the best AChE inhibitor was the pyrrolidine alpha-aminonitrile 3 (IC50 = 42 muM), followed by the piperidine alpha-aminonitriles 2 and 6 (IC50 = 45 muM and IC50 = 51 muM, respectively), and the compound 7 (IC50 = 51 muM). 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.