New Bisquaternary Isoquinolinium Inhibitors of Brain Cholinesterases - Synthesis and Anticholinesterase Activity

Jiri      Binder; Martin      Paar; Daniel      Jun; Miroslav      Pohanka; Martina      Hrabinova; Veronika      Opletalova; Kamil      Kuca

Abstract

Alzheimers 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.

Keywords: Quinolinium, Quaternary compounds, Inhibitor, Cholinesterase, Alzheimer's disease, Anticholinergic