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

•Application of rational design for the generation of new series of α-aminonitriles.•Twenty novel girgensohnine analogs were synthesized and characterized.•All the synthesized compounds inhibited AChE, highlighting compounds 2–4 and 6–8.•Larvicidal activity of six analogs on Aedes aegypti mosquitoes, were evaluated.•Compounds 2 and 7 exhibit the highest larvicidal activity.

Girgensohnine alkaloid was used as a natural model in the design and generation of new alkaloid-like α-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 α-aminonitriles could be considered as AChEIs with micromolar IC50 values ranging from 42.0 to 478.0 μM (10.3–124.0 μg/mL). Among this series, the best AChE inhibitor was the pyrrolidine α-aminonitrile 3 (IC50 = 42 μM), followed by the piperidine α-aminonitriles 2 and 6 (IC50 = 45 μM and IC50 = 51 μM, respectively), and the compound 7 (IC50 = 51 μM). 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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide