Chemoselective Hydrogenation of 6-Alkynyl-3-fluoro-2-pyridinaldoximes: Access to First-in-Class 6-Alkyl-3-Fluoro-2-pyridinaldoxime Scaffolds as New Reactivators of Sarin-Inhibited Human Acetylcholinesterase with Increased Blood-Brain Barrier Permeability.
3-fluoro-2-pyridinaldoximes
blood-brain barrier permeability
chemical warfare agents
chemoselective hydrogenation
synthesis design
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
ISSN: 1521-3765
Titre abrégé: Chemistry
Pays: Germany
ID NLM: 9513783
Informations de publication
Date de publication:
20 Nov 2020
20 Nov 2020
Historique:
received:
24
04
2020
pubmed:
8
7
2020
medline:
17
2
2021
entrez:
8
7
2020
Statut:
ppublish
Résumé
Novel 6-alkyl- and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesised by using a mild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2-pyridinaldoxime scaffolds, without altering the reducible, unprotected, sensitive oxime functionality and the C-F bond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximes may find medicinal application as antidotes to organophosphate poisoning. Indeed, one low-molecular-weight compound exhibited increased affinity for sarin-inhibited acetylcholinesterase (hAChE) and greater reactivation efficiency or resurrection for sarin-inhibited hAChE, compared with those of 2-pyridinaldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]methoxy}methyl)-2-[(hydroxyimino)methyl]pyridinium chloride (HI-6), two pyridinium salts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showed increased in vitro blood-brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promising features of novel low-molecular-weight alkylfluoropyridinaldoxime open up a new era for the design, synthesis and discovery of central non-quaternary broad spectrum reactivators for organophosphate-inhibited cholinesterases.
Identifiants
pubmed: 32633095
doi: 10.1002/chem.202002012
doi:
Substances chimiques
Cholinesterase Inhibitors
0
Cholinesterase Reactivators
0
Oximes
0
Pyridinium Compounds
0
pyridine-2-aldoxime
8PN0640Z70
Sarin
B4XG72QGFM
Acetylcholinesterase
EC 3.1.1.7
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
15035-15044Subventions
Organisme : Agence Nationale de la Recherche ANR
ID : ANR 15-CE39-0012
Organisme : Agence Nationale de la Recherche
ID : 17-CE39-0012-01
Organisme : Direction Générale de l'Armement (DGA) and Service de Santé des Armées (SSA) of the French Ministry of Armed Forces
ID : NBC-5-C-4210
Informations de copyright
© 2020 Wiley-VCH GmbH.
Références
C. M. Timperley, J. E. Forman, M. Abdollahi, A. S. Al-Amri, A. Baulig, D. Benachour, V. Borrett, F. A. Cariño, M. Geist, D. Gonzalez, W. Kane, Z. Kovarik, R. Martínez-Álvarez, N. M. Fusaro Mourão, S. Neffe, S. K. Raza, V. Rubaylo, A. G. Suárez, K. Takeuchi, C. Tang, F. Trifirò, F. Mauritz van Straten, P. S. Vanninen, S. Vučinić, V. Zaitsev, M. Zafar-Uz-Zaman, M. S. Zina, S. Holen, Toxicology 2019, 415, 56-59.
D. E. Lorke, G. A. Petroianu, Front. Neurosci. 2019, 13, 1-13;
E. J. Mew, P. Padmanathan, F. Konarasen, M. Eddlestion, S.-S. Chang, M. R. Phillips, D. Gunnel, J. Affective Disord. 2017, 219, 93-104.
R. C. Gupta in Toxicology of Organophosphate and Carbamate Compounds (Ed.: R. C. Gupta), Elsevier Academic Press, Massachusetts, 2006a, pp. 5-24.
E. Antonijevic, J. Kotur-Stevuljevic, K. Musilek, A. Kosvancova, K. Kuca, D. Djukic-Cosic, V. Spasojevic-Kalimanovska, B. Antonijevic, Arch. Toxicol. 2018, 92, 745-757;
G. A. Petroianu, Pharmazie 2014, 69, 780-784;
T. Myhrer, P. Aas, Neurosci. Biobehav. Rev. 2016, 71, 657-670;
P. Masson, F. Nachon, J. Neurochem. 2017, 142, 26-40;
J. Kassa, C. M. Timperley, M. Bird, R. L. Williams, A. C. Gree, J. E. H. Tattersall, Toxicology 2018, 408, 95-100.
G. Mercey, T. Verdelet, J. Renou, M. Kliachyna, R. Baati, F. Nachon, L. Jean, P.-Y. Renard, Acc. Chem. Res. 2012, 45, 756-766;
A. J. Franjesevic, S. B. Sillart, J. M. Beck, S. Vyas, S. Christopher, C. M. Hadad, Chem. Eur. J. 2019, 25, 5337-5371;
S. Costanzi, J. H. Machado, M. Mitchell, ACS Chem. Neurosci. 2018, 9, 873-885;
F. Worek, H. Tielmann, T. Wille, Arch. Toxicol. 2020, 94, 2275-2292.
F. Eyer, V. Meischner, D. Kiderlen, H. Thiermann, F. Worek, M. Haberkorn, Toxicol. Rev. 2003, 22, 143-163;
M. Balali-Mood, K. Balali-Mood, Arch. Iran. Med. 2008, 11, 65-89;
G. Petroianu, L. M. Toomes, A. Petroianu, W. Bergler, R. Rufer, J. Appl. Toxicol. 1998, 18, 293-298;
G. A. Petroianu, Eur. J. Emerg. Med. 2005, 12, 102-103;
B. Antonijevic, M. P. Stojiljkovic, Clin. Med. Res. 2007, 5, 71-82;
H. Hrabetz, H. Thiermann, N. Felgenhauer, T. Zilker, B. Haller, J. Nahrig, Chem.-Biol. Interact. 2013, 206, 561-568.
F. Worek, H. Thiermann, T. Wille, Chem.-Biol. Interact. 2016, 259, 93-98.
M. Kloske, Z. Witkiewicz, Chemosphere 2019, 221, 672-682;
J. A. Vale, T. C. Marrs, R. L. Maynard, Clin. Toxicol. 2018, 56, 1093-1097;
T. C. C. Franca, D. A. S. Kitagawa, S. F. de A. Cavalcante, J. A. V. da Silva, E. Nepovimova, K. Kuca, Int. J. Mol. Sci. 2019, 20, 1222;
K. Kuca, E. Nepovimova, Australasian Med. J. 2019, 12, 49-52.
L. Louise-Leriche, E. Pàunescu, G. Saint-André, R. Baati, A. Romieu, A. Wagner, P. Y. Renard, Chem. Eur. J. 2010, 16, 3510-3523;
G. Saint-André, M. Kliachyna, S. Kodepelly, L. Louise-Leriche, E. Gillon, P. Y. Renard, F. Nachon, R. Baati, A. Wagner, Tetrahedron 2011, 67, 6352-6361.
G. Mercey, T. Verdelet, G. Saint-Andre, E. Gillon, A. Wagner, R. Baati, L. Jean, F. Nachon, P. Y. Renard, Chem. Commun. 2011, 47, 5295-5297;
G. Mercey, J. Renou, T. Verdelet, M. Kliachyna, R. Baati, E. Gillon, M. Arboleas, M. Loiodice, F. Nachon, L. Jean, P. Y. Renard, J. Med. Chem. 2012, 55, 10791-10795;
J. Renou, G. Mercey, T. Verdelet, E. Paunescu, E. Gillon, M. Arboleas, M. Loiodice, M. Kliachyna, R. Baati, F. Nachon, L. Jean, P. Y. Renard, Chem.-Biol. Interact. 2013, 203, 81-84;
J. Renou, M. Loiodice, M. Arboleas, R. Baati, L. Jean, F. Nachon, P. Y. Renard, Chem. Commun. 2014, 50, 3947-3950;
M. Kliachyna, G. Santoni, V. Nussbaum, J. Renou, B. Sanson, J. P. Colletier, M. Arboléas, M. Loiodice, M. Weik, L. Jean, P. Y. Renard, F. Nachon, R. Baati, Eur. J. Med. Chem. 2014, 78, 455-467;
J. Renou, J. Dias, G. Mercey, T. Verdelet, C. Rousseau, A. J. Gastellier, M. Arboleas, M. Touvrey-Loiodice, R. Baati, L. Jean, F. Nachon, P. Y. Renard, RSC Adv. 2016, 6, 17929-17940;
A.-G. Calas, A.-S. Hanak, N. Jaffré, A. Nervo, J. Dias, C. Rousseau, C. Courageux, X. Brazzolotto, P. Villa, A. Obrecht, J.-F. Goossens, C. Landry, J. Hachani, F. Gosselet, M.-P. Dehouck, J. Yerri, M. Klyachina, R. Baati, F. Nachon, Biomolecules 2020, 10, 858.
T. Zorbaz, A. Braïki, N. Maraković, J. Renou, E. de la Mora, N. Maček Hrvat, M. Katalinić, I. Silman, J. L. Sussman, G. Mercey, C. Gomez, R. Mougeot, B. Pérez, R. Baati, F. Nachon, M. Weik, L. Jean, Z. Kovarik, P. Y. Renard, Chem. Eur. J. 2018, 24, 9675-9691;
G. Santoni, J. de Sousa, E. de la Mora, J. Dias, L. Jean, J. L. Sussman, I. Silman, P. Y. Renard, R. C. D. Brown, M. Weik, R. Baati, F. Nachon, J. Med. Chem. 2018, 61, 7630-7639.
M. C. de Koning, M. van Grol, D. Noort, Tox. Lett. 2011, 206, 54-59;
M. C. de Koning, M. J. A. Joosen, F. Worek, F. Nachon, M. van Grol, S. D. Klaassen, D. P. W. Alkema, T. Wille, H. M. de Bruijn, J. Med. Chem. 2017, 60, 9376-9392.
T. Zorbaz, D. Malinak, N. Maraković, N. Maček Hrvat, A. Zandona, M. Novotny, A. Skarka, R. Andrys, M. Benkova, O. Soukup, M. Katalinić, K. Kuca, Z. Kovarik, K. Musilek, J. Med. Chem. 2018, 61, 10753-10766;
T. Zorbaz, D. Malinak, K. Kuca, K. Musilek, Z. Kovarik, Chem.-Biol. Interact. 2019, 307, 16-20.
F. S. Katz, S. Pecic, T. H. Tran, I. Trakht, L. Schneider, Z. Zhu, L. Ton-That, M. Luzac, V. Zlatanic, S. Damera, J. Mac Donald, D. W. Landry, L. Tong, M. N. Stojanovic, ChemBioChem 2015, 16, 2205-2215;
M. C. de Koning, G. Horn, F. Worek, Eur. J. Med. Chem. 2018, 157, 151-160;
C. Linn Cadieux, H. Wang, Y. Zhang, J. A. Koenig, T. M. Shih, J. Mac Donough, J. Koh, D. Cerasoli, Chem.-Biol. Interact. 2016, 259, 133-141.
K. Muller, C. Faeh, F. Diederich, Science 2007, 317, 1881-1886;
P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications, 2nd ed., Wiley-VCH, Weinheim, 2013;
J. Wang, M. Sanchez-Rosello, J. Acenă, C. Del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432-2506;
E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med. Chem. 2015, 58, 8315-8359;
S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320-330;
W. K. Hagmann, J. Med. Chem. 2008, 51, 4359-4369;
N. A. Meanwell, J. Med. Chem. 2011, 54, 2529-2591.
M. Timperley, R. E. Banks, I. M. Young, R. N. Haszeldine, J. Fluorine Chem. 2011, 132, 541-547;
H. C. Jeong, N. S. Kang, N. J. Park, E. K. Yumb, Y. S. Jung, Bioorg. Med. Chem. Lett. 2009, 19, 1214-1217;
H. C. Jeong, N. S. Kang, N. J. Park, E. K. Yum, Y. S. Jung, Bioorg. Med. Chem. 2009, 17, 6213-6217.
Y. Jagadeesh, R. Baati, Eur. J. Org. Chem. 2018, 4161-4165.
K. D. Baucom, A. S. Guram, C. J. Borths, Synlett 2015, 26, 201-204;
I. Tsukamoto, H. Koshio, T. Kuramochi, C. Saitoh, H. Yanai-Inamura, C. Kitada-Nozawa, E. Yamamoto, T. Yatsu, Y. Shimada, S. Sakamoto, S. I. Tsukamoto, Bioorg. Med. Chem. 2009, 17, 3130-3141.
D. Uredi, D. Reddy Motati, E. B. Watkins, Chem. Commun. 2019, 55, 3270;
T. J. Donohoe, C. R. Jones, A. F. Kornahrens, L. C. Barbosa, L. J. Walport, M. R. Tatton, M. O'Hagan, A. H. Rathi, D. B. Baker, J. Org. Chem. 2013, 78, 12338-12350;
P. Fu, S. Wang, K. Hong, X. Li, P. Liu, Y. Wang, W. Zhu, J. Nat. Prod. 2011, 74, 1751-1756;
Z. Song, X. Huang, W. Yi, W. Zhang, Org. Lett. 2016, 18, 5640-5643.
The chemical synthesis of 14 is described in the Experimental Section.
R. Cecchelli, S. Aday, E. Sevin, C. Almeida, M. Culot, L. Dehouck, C. Coisne, B. Engelhardt, M. P. Dehouck, L. Ferreira, PLoSOne 2014, 9.
D. C. Pedroso, A. Tellechea, L. Moura, I. Fidalgo-Carvalho, J. Duarte, E. Carvalho, L. Ferreira, PLoS One 2011, 6.
A. Siflinger-Birnboim, P. J. Del Vecchio, J. A. Cooper, F. A. Blumenstock, J. M. Shepard, A. B. Malik, J. Cell Physiol. 1987, 132, 111-117.
S. Gustafsson, V. Lindström, M. Ingelsson, M. Hammarlund-Udenaes, S. Syvänen, Neuropharmacology 2018, 128, 482-491.
B. M. Best, S. L. Letendre, E. Brigid, D. B. Clifford, A. C. Collier, B. B. Gelman, J. C. McArthur, J. A. Mc Cutchan, D. M. Simpson, R. Ellis, E. V. Capparelli, I. Grant, AIDS 2009, 23, 83-87.