engleski

Application of "click chemistry" in the synthesis of new reactivators of inhibited acetylcholinesterase (AChE)

Organophosphorus pesticides (e.g. Parathion, Chlorpyrifos) and chemical warfare nerve agents (e.g. Sarin, Tabun, VX) are potent irreversible inhibitors of synaptic AChE, causing cholinergic overstimulation and death due to respiratory system failure. The current standard treatment consists of the combination of atropine and an AChE reactivator. Two currently approved drugs are HI-6 and 2-PAM (Scheme 1). Unfortunately, their potency is strongly dependant upon the type of toxic agent and none of them possess sufficient activity toward reactivation of inhibited AChE by wide range of organophosphorus. Application of the [3+2] cycloaddition reaction between alkynes and azides (“ Click reaction” ) as a combinatorial approach allows for the fast and reliable synthesis of libraries of new reactivators. Initial screening toward reactivation of Paraoxon- or Tabun- inhibited AChE revealed high activity, comparable to that of HI-6 and 2-PAM, for compounds possessing oxime group in ortho position of a pyridine– based scaffold. Subsequent SAR studies led to the observation that bi-functional oximes exhibit even higher activity than their mono-functional counterparts. A library of bisoximes was prepared possessing linkers of various lengths designed to control the distance between the two pyridinium quaternary centers. Reactivation studies showed that a distance of 8 atoms between both quaternary nitrogens yields the most optimal compound for the reactivation of Paraoxon-inhibited AChE as well as of tabun-inhibited AChE.

click-chemistry; 2-PAM; HI-6; reactivation; tabun sarin; VX; parathion; chlorpyrifos

nije evidentirano