Preparation and in vitro screening of symmetrical bispyridinium cholinesterase inhibitors bearing different connecting linkage-initial study for Myasthenia gravis implications.
Reversible inhibitors (e.g., pyridostigmine bromide, neostigmine bromide) of carbamate origin are used in the early treatment of Myasthenia gravis (MG) to block acetylcholinesterase (AChE) native function and conserve efficient amount of acetylcholine for decreasing number of nicotinic receptors. Carbamate inhibitors are known for many undesirable side effects related to the reversible inhibition of AChE. In contrast, this paper describes 20 newly prepared bispyridinium inhibitors of potential concern for MG. Although some compounds from this series have been known before, they were not assayed for cholinesterase inhibition yet. The newly prepared compounds were evaluated in vitro on human erythrocyte AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC(50) and compared to standard carbamate drugs. Three compounds presented promising inhibition (in muM range) of both enzymes in vitro similar to the used standards. The novel inhibitors did not present selectivity between AChE and BChE. Two newly prepared compounds were chosen for docking studies and confirmed apparent pi-pi or pi-cationic interactions aside enzyme's catalytic sites. The kinetics assay confirmed non-competitive inhibition of AChE by two best newly prepared compounds.
Department of Toxicology, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. musilek@pmfhk.cz
Kamil
K
Musilek
Marketa
M
Komloova
Vlasta
V
Zavadova
Ondrej
O
Holas
Martina
M
Hrabinova
Miroslav
M
Pohanka
Vlastimil
V
Dohnal
Florian
F
Nachon
Martin
M
Dolezal
Kamil
K
Kuca
Young-Sik
YS
Jung
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry / Q000627:therapeutic use; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D009157:Myasthenia Gravis / Q000188:drug therapy*; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase