-
Je něco špatně v tomto záznamu ?
Uncharged mono- and bisoximes: In search of a zwitterion to countermeasure organophosphorus intoxication
L. Gorecki, A. Markova, V. Hepnarova, N. Zivna, L. Junova, M. Hrabinova, J. Janousek, T. Kobrlova, L. Prchal, D. Jun, O. Soukup, G. Horn, F. Worek, J. Marek, J. Korabecny
Chemico-biological interactions.
2024 ;
394 (-) :
110941.
[pub] 20240316
Jazyk angličtina Země Irsko
Typ dokumentu časopisecké články
Perzistentní odkaz
https://www.medvik.cz/link/bmc24014115
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota chemie farmakologie MeSH
- butyrylcholinesterasa * metabolismus chemie MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- kinetika MeSH
- lidé MeSH
- organofosforové sloučeniny chemie MeSH
- otrava organofosfáty * farmakoterapie MeSH
- oximy * chemie farmakologie MeSH
- reaktivátory cholinesterasy * chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The current study imposes a new class of organophosphorus (OP)-inhibited cholinesterase reactivators by conceptualizing a family of asymmetric bisoximes with various reactivating scaffolds. Several novel nucleophilic warheads were investigated, putting forward 29 novel reactivating options, by evaluating their nucleophilicity and ability to directly decompose OP compounds. Adopting the so-called zwitterionic strategy, 17 mono-oxime and nine bisoxime reactivators were discovered with major emphasis on the bifunctional-moiety approach. Compounds were compared with clinically used standards and other known experimentally highlighted reactivators. Our results clearly favor the concept of asymmetric bisoximes as leading reactivators in terms of efficacy and versatility. These top-ranked compounds were characterized in detail by reactivation kinetics parameters and evaluated for potential CNS availability. The highlighted molecules 55, 57, and 58 with various reactivating warheads, surpassed the reactivating potency of pralidoxime and several notable uncharged reactivators. The versatility of lead drug candidate 55 was also inspected on OP-inhibited butyrylcholinesterase, revealing a much higher rate compared to existing clinical antidotes.
Citace poskytuje Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc24014115
- 003
- CZ-PrNML
- 005
- 20240905133412.0
- 007
- ta
- 008
- 240725e20240316ie f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.cbi.2024.110941 $2 doi
- 035 __
- $a (PubMed)38493910
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a ie
- 100 1_
- $a Gorecki, Lukas $u University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: lukas.gorecki@unob.cz
- 245 10
- $a Uncharged mono- and bisoximes: In search of a zwitterion to countermeasure organophosphorus intoxication / $c L. Gorecki, A. Markova, V. Hepnarova, N. Zivna, L. Junova, M. Hrabinova, J. Janousek, T. Kobrlova, L. Prchal, D. Jun, O. Soukup, G. Horn, F. Worek, J. Marek, J. Korabecny
- 520 9_
- $a The current study imposes a new class of organophosphorus (OP)-inhibited cholinesterase reactivators by conceptualizing a family of asymmetric bisoximes with various reactivating scaffolds. Several novel nucleophilic warheads were investigated, putting forward 29 novel reactivating options, by evaluating their nucleophilicity and ability to directly decompose OP compounds. Adopting the so-called zwitterionic strategy, 17 mono-oxime and nine bisoxime reactivators were discovered with major emphasis on the bifunctional-moiety approach. Compounds were compared with clinically used standards and other known experimentally highlighted reactivators. Our results clearly favor the concept of asymmetric bisoximes as leading reactivators in terms of efficacy and versatility. These top-ranked compounds were characterized in detail by reactivation kinetics parameters and evaluated for potential CNS availability. The highlighted molecules 55, 57, and 58 with various reactivating warheads, surpassed the reactivating potency of pralidoxime and several notable uncharged reactivators. The versatility of lead drug candidate 55 was also inspected on OP-inhibited butyrylcholinesterase, revealing a much higher rate compared to existing clinical antidotes.
- 650 12
- $a oximy $x chemie $x farmakologie $7 D010091
- 650 12
- $a reaktivátory cholinesterasy $x chemie $x farmakologie $7 D002801
- 650 12
- $a butyrylcholinesterasa $x metabolismus $x chemie $7 D002091
- 650 _2
- $a lidé $7 D006801
- 650 12
- $a otrava organofosfáty $x farmakoterapie $7 D062025
- 650 _2
- $a acetylcholinesterasa $x metabolismus $7 D000110
- 650 _2
- $a antidota $x chemie $x farmakologie $7 D000931
- 650 _2
- $a kinetika $7 D007700
- 650 _2
- $a cholinesterasové inhibitory $x chemie $x farmakologie $7 D002800
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a organofosforové sloučeniny $x chemie $7 D009943
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Markova, Aneta $u University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Hospital Pharmacy, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
- 700 1_
- $a Hepnarova, Vendula $u University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
- 700 1_
- $a Zivna, Natalie $u University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
- 700 1_
- $a Junova, Lucie $u University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
- 700 1_
- $a Hrabinova, Martina $u University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
- 700 1_
- $a Janousek, Jiri $u University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
- 700 1_
- $a Kobrlova, Tereza $u University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
- 700 1_
- $a Prchal, Lukas $u University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
- 700 1_
- $a Jun, Daniel $u University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
- 700 1_
- $a Soukup, Ondrej $u University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
- 700 1_
- $a Horn, Gabriele $u Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany
- 700 1_
- $a Worek, Franz $u Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany
- 700 1_
- $a Marek, Jan $u University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; University of Defence, Military Faculty of Medicine, Department of Epidemiology, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
- 700 1_
- $a Korabecny, Jan $u University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: jan.korabecny@fnhk.cz
- 773 0_
- $w MED00002111 $t Chemico-biological interactions $x 1872-7786 $g Roč. 394 (20240316), s. 110941
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/38493910 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y - $z 0
- 990 __
- $a 20240725 $b ABA008
- 991 __
- $a 20240905133406 $b ABA008
- 999 __
- $a ok $b bmc $g 2143723 $s 1225981
- BAS __
- $a 3
- BAS __
- $a PreBMC-MEDLINE
- BMC __
- $a 2024 $b 394 $c - $d 110941 $e 20240316 $i 1872-7786 $m Chemico-biological interactions $n Chem Biol Interact $x MED00002111
- LZP __
- $a Pubmed-20240725
