title: Novel potent pyridoxine-based inhibitors of AChE and BChE, structural analogs of pyridostigmine, with improved in vivo safety profile.
abstract: We report a novel class of carbamate-type ChE inhibitors, structural analogs of pyridostigmine. A small library of congeneric pyridoxine-based compounds was designed, synthesized and evaluated for AChE and BChE enzymes inhibition in vitro. The most active compounds have potent enzyme inhibiting activity with IC50 values in the range of 0.46-2.1μM (for AChE) and 0.59-8.1μM (for BChE), with moderate selectivity for AChE comparable with that of pyridostigmine and neostigmine. Acute toxicity studies using mice models demonstrated excellent safety profile of the obtained compounds with LD50 in the range of 22-326mg/kg, while pyridostigmine and neostigmine are much more toxic (LD50 3.3 and 0.51mg/kg, respectively). The obtained results pave the way to design of novel potent and safe cholinesterase inhibitors for symptomatic treatment of neuromuscular disorders.
authors.affiliation: Kazan (Volga region) Federal University, Kremlyovskaya 18, 420008 Kazan, Russia.
authors.forename: Alexey D
authors.initials: AD
authors.lastname: Strelnik
authors.affiliation: Kazan (Volga region) Federal University, Kremlyovskaya 18, 420008 Kazan, Russia.
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Petukhov
authors.affiliation: Kazan (Volga region) Federal University, Kremlyovskaya 18, 420008 Kazan, Russia; A.E. Arbuzov Institute of Organic and Physical Chemistry; KazSC, Russian Academy of Sciences, Arbuzova 8, 420088 Kazan, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Zueva
authors.affiliation: Kazan (Volga region) Federal University, Kremlyovskaya 18, 420008 Kazan, Russia; A.E. Arbuzov Institute of Organic and Physical Chemistry; KazSC, Russian Academy of Sciences, Arbuzova 8, 420088 Kazan, Russia.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Zobov
authors.affiliation: Kazan (Volga region) Federal University, Kremlyovskaya 18, 420008 Kazan, Russia; A.E. Arbuzov Institute of Organic and Physical Chemistry; KazSC, Russian Academy of Sciences, Arbuzova 8, 420088 Kazan, Russia.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Petrov
authors.affiliation: Kazan (Volga region) Federal University, Kremlyovskaya 18, 420008 Kazan, Russia; Kazan Institute of Biochemistry and Biophysics, Lobachevsky St. 2/31, Kazan 420111, Russia.
authors.forename: Evgeny E
authors.initials: EE
authors.lastname: Nikolsky
authors.affiliation: Kazan (Volga region) Federal University, Kremlyovskaya 18, 420008 Kazan, Russia; Institute of Physiologically Active Compounds of Russian Academy of Sciences, Severnyi pr. 1, Chernogolovka, Moscow Reg. 142432, Russia.
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Balakin
authors.affiliation: Institute of Physiologically Active Compounds of Russian Academy of Sciences, Severnyi pr. 1, Chernogolovka, Moscow Reg. 142432, Russia.
authors.forename: Sergey O
authors.initials: SO
authors.lastname: Bachurin
authors.affiliation: Kazan (Volga region) Federal University, Kremlyovskaya 18, 420008 Kazan, Russia. Electronic address: yurii.shtyrlin@gmail.com.
authors.forename: Yurii G
authors.initials: YG
authors.lastname: Shtyrlin
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D007928:Lethal Dose 50; D051379:Mice; D011485:Protein Binding; D011729:Pyridostigmine Bromide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D011736:Pyridoxine / Q000737:chemistry*; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D011736:Pyridoxine; D011729:Pyridostigmine Bromide
keywords: Acetylcholinesterase (AChE) inhibitors; Carbamate cholinesterase inhibitors; Neuromuscular disorders treatment; Pyridostigmine analogs; Substituted pyridoxines