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 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.
Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, Bucaramanga A.A. 678, Colombia.
Aurora L
AL
Carreño Otero
Grupo de investigaciones Ambientales para el Desarrollo Sostenible, Universidad Santo Tomás de Aquino, Bucaramanga A.A. 678, Colombia.
Leonor Y
LY
Vargas Méndez
Centro de Investigaciones en Enfermedades Tropicales y Grupo de Investigación en Enfermedades Infecciosas y Metabólicas, Escuela de Medicina, Universidad Industrial de Santander, Bucaramanga A.A. 678, Colombia.
Jonny E
JE
Duque L
Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, Bucaramanga A.A. 678, Colombia. Electronic address: kouznet@uis.edu.co.
Vladimir V
VV
Kouznetsov
D000110:Acetylcholinesterase / Q000378:metabolism*; D000330:Aedes / Q000737:chemistry*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007303:Insect Vectors / Q000737:chemistry*; D007306:Insecticides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009570:Nitriles; D011759:Pyrrolidines; C000593737:girgensohnine; D000110:Acetylcholinesterase
AChE inhibition; Aedes aegypti larvae; Larvicidal activity; Strecker reaction; α-Aminonitriles