Novel pyridinium derivatives as inhibitors for acetylcholinesterase

The carbamate 1-(methyl-3-(N,N-dimethylcarbamoyloxy)-2-pyridylmethylene)-4 -(4-phenyl) diazinecarboxamide chloride (MHP 133) is the parent for a new class of pyridinium salts which inhibit acetylcholinesterase (AChE) in vitro as well as in vivo. Fourteen new derivatives of MHP 133 have been synthesized with the intention of improving their hydrophobicity while maintaining their propensity to inhibit acetylcholinesterase. Upon prolonged incubation with AChE, the pyridinium salts exhibit progressive time-dependent inhibition according to first order kinetics with kobs/[I] values ranging from 3 to 345 M-1s-1. The enzyme did not regain any activity after prolonged incubation with the inhibitors (1 day). The partition coefficients for each inhibitor were evaluated in octanol/water in order to determine their hydrophobic character as hydrophobicity is a key prerequisite for crossing the blood brain barrier.