Synthesis and biological evaluation of novel uncharged cholinesterase reactivator against nerve agent intoxication

Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mojmír Vaněk Supervisor: doc. PharmDr. Jaroslav Roh Ph.D. Advisors: PharmDr. Jan Korábečný Ph.D.; PharmDr. Vendula Hepnarová Ph.D. Title of diploma thesis: Synthesis and biological evaluation of novel uncharged cholinesterase reactivator against nerve agent intoxication Nerve agents (NPL) and pesticids are strongly toxic organophosphorus compounds with high affinity to acetylcholinesterase (AChE) enzyme. This enzyme is present in CNS and neuromuscular synapses. The intoxication leads into an acute cholinergic crisis, which can ultimately results into death. The therapy must be quick and includes application of atropine, reactivators of AChE and diazepam. Among the commonly used AChE reactivators, mono- or bis- quarternary aldoximes cen be found. These compounds are permanently charged, so their penetration through the blood-brain barrier (HEB) is very limited (up to 10 %, often only 1-3 %). Within the diploma thesis, a non quarternary AChE reactivator has been developed by multiple-steps synthesis approach. This compound, denoted as K1396, would exert high ability to penetrate through HEB. In vitro assessments of his capability to reactivate AChE has been carried out by method of Ellman...