- Design, synthesis, acetylcholinesterase inhibition and larvicidal activity of girgensohnine analogs on Aedes aegypti, vector of dengue fever
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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 IC 50 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.
- Carre?o Otero, Aurora L.,Vargas Méndez, Leonor Y.,Duque L., Jonny E.,Kouznetsov, Vladimir V.
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p. 392 - 400
(2014/04/17)
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- Steric Inhibition of Synergistic Radical Stabilizing Effects
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Equilibrium acidities in Me2SO for 14 α-N-morpholinyl-, 6 α-N-piperidinyl-, and 7 α-cyclohexylarylacetonitriles and the oxidation potentials of their conjugate bases have been determined.The increased pKHA values by about 2 units observed in these systems, relative to the corresponding arylacetonitriles, is ascribed to the presence of increased steric constraints in the anions.Hammett plots revealed larger ρ values than for arylacetonitriles (6-7 versus 5.5), pointing to an increased negative charge density on the benzylic carbon atoms in the anions.A plot of anion oxidation potentials, Eox(A-), versus pKHA for the α-N-morpholinylarylacetonitriles was linear with a slope near unity, showing that remote substituents for the most part have very little effect on radical stabilities.A 5 and 6 kcal/mol lowering of the BDE of the acidic C-H bond caused by replacing the cyclohexyl group in α-cyclohexylphenylacetonitrile by α-N-morpholinyl or N-piperidinyl groups, respectively, is attributed to the strong donor properties of these amino functions.The effects are only about one-third as large, however, as similar effects in R2NCH2COPh, where the steric effect of Ph is absent and a synergistic effect is believed to be operative.
- Bordwell, F. G.,Bausch, Mark J.,Cheng, Jin-Pei,Cripe, Thomas H.,Lynch, Tsuei-Yun,Mueller, Mark E.
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