67258-24-6Relevant academic research and scientific papers
Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage - Implications for early Myasthenia gravis treatment
Musilek, Kamil,Komloova, Marketa,Holas, Ondrej,Hrabinova, Martina,Pohanka, Miroslav,Dohnal, Vlastimil,Nachon, Florian,Dolezal, Martin,Kuca, Kamil
experimental part, p. 811 - 818 (2011/03/19)
Inhibitors of acetylcholinesterase are compounds widely used in the treatment of various diseases, such as Alzheimer's disease, glaucoma and Myasthenia gravis (MG). Compounds used in the therapy of MG posses a positive charge in the molecule to ensure peripheral effect of action and minimal blood-brain barrier penetration. The most prescribed carbamate inhibitors are however known for many severe side effects related to the carbamylation of AChE. This paper describes preparation and in vitro evaluation of 20 newly prepared bis-isoquinolinium inhibitors of potential concern for MG. The newly prepared compounds were evaluated in vitro on human recombinant AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC 50 and compared to chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. Three novel compounds presented promising inhibition (in nM range) of both enzymes in vitro better or similar to edrophonium and BW284c51, but worse to ambenonium. The novel inhibitors did not present higher selectivity toward AChE or BChE. The kinetic assay confirmed non-competitive inhibition of hAChE by two selected promising novel compounds. Two newly prepared compounds were also chosen for docking studies that confirmed apparent π-π or π-cationic interactions aside the cholinesterases catalytic sites. The SAR findings were discussed.
New bisquaternary isoquinolinium inhibitors of brain cholinesterases - Synthesis and anticholinesterase activity
Binder, Jiri,Paar, Martin,Jun, Daniel,Pohanka, Miroslav,Hrabinova, Martina,Opletalova, Veronika,Kuca, Kamil
experimental part, p. 1 - 4 (2011/01/03)
Alzheimer's disease (AD) is one of the most discussed diseases of present time. Because of the aging of our population it is high threat for future. Due to this, new drugs combating AD are still developed. In this study, twelve bisquaternary isoquinolinium derivatives differing in the linker between two heteroarenium rings were synthesized and tested for their potency to inhibit brain cholinesterases. According to the obtained in vitro results, the anticholinesterase activity grew up with the length of the connection chain. Possible binding to the enzyme cavity was described using software Autodock. Moreover, LogP and molecular volume of prepared compounds were predicted. As resulted, the highest probability of synthesized compounds to penetrate blood-brain barrier could be expected for the compound with linker having eight methylenes.
