Preparation, in vitro evaluation and molecular modelling of pyridinium-quinolinium/isoquinolinium non-symmetrical bisquaternary cholinesterase inhibitors.
Two series of non-symmetrical bisquaternary pyridinium-quinolinium and pyridinium-isoquinolinium compounds were prepared as molecules potentially applicable in myasthenia gravis treatment. Their inhibitory ability towards human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase was determined and the results were compared to the known effective inhibitors such as ambenonium dichloride, edrophonium bromide and experimental compound BW284C51. Two compounds, 1-(10-(pyridinium-1-yl)decyl)quinolinium dibromide and 1-(12-(pyridinium-1-yl)dodecyl)quinolinium dibromide, showed very promising affinity for acetylcholinesterase with their IC50 values reaching nM inhibition of acetylcholinesterase. These most active compounds also showed satisfactory selectivity towards acetylcholinesterase and they seem to be very promising as leading structures for further modifications and optimization. Two of the most promising compounds were examined in the molecular modelling study in order to find the possible interactions between the ligand and tested enzyme.
Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Inorganic and Organic Chemistry, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic; University of Jan Evangelista Purkynje, Faculty of Science, Department of Chemistry, Ceske mladeze 8, 400 96 Usti nad Labem, Czech Republic.
Marketa
M
Komloova
Anna
A
Horova
Martina
M
Hrabinova
Daniel
D
Jun
Martin
M
Dolezal
Jarmila
J
Vinsova
Kamil
K
Kuca
Kamil
K
Musilek
D000110:Acetylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D011726:Pyridinium Compounds; D011806:Quinolinium Compounds; D011994:Recombinant Proteins; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
Cholinesterase; In vitro; Inhibitor; Molecular modelling; Myasthenia gravis