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

Autor: Carreño Otero AL; Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, Bucaramanga A.A. 678, Colombia., Vargas Méndez LY; Grupo de investigaciones Ambientales para el Desarrollo Sostenible, Universidad Santo Tomás de Aquino, Bucaramanga A.A. 678, Colombia., Duque L JE; 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., Kouznetsov VV; Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, Bucaramanga A.A. 678, Colombia. Electronic address: kouznet@uis.edu.co.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2014 May 06; Vol. 78, pp. 392-400. Date of Electronic Publication: 2014 Mar 24.
DOI: 10.1016/j.ejmech.2014.03.067
Abstrakt: 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.
(Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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