REPUBLIC OF SERBIA

MINISTRY OF DEFENCE

www.mod.gov.rs

MINISTRY OF DEFENCE

Material Resources Sector

Defensive Technologies Department

Military Technical Institute

www.vti.mod.gov.rs

DESIGN AND SYNTHESIS OF NOVEL AROYLACRYLIC ACID PHENYLAMID DERIVATIVES for reversible inhibition of cholinesterases

MAJA D. VITOROVIĆ-TODOROVIĆ

Military Technical Institute, Belgrade, mvitod@chem.bg.ac.rs

tamarA B. vujatović

Faculty of Chemistry, University of Belgrade, tamara.vujatovic@gmail.com

MARINA S. ILIĆ

Military Technical Institute, Belgrade, marinailic1970@gmail.com

Abstract: Organophosphorous chemical warfare agents (i.e. nerve agents) exhibit their toxic effects mainly through covalent irreversible inhibition of acetylcholinesterase (EC 3.1.1.7), an enzyme which terminates cholinergic neurotransmission, by hydrolyzing acetylcholine at nerve and nerve-muscle junctions. The reversible inhibition of AChE was suggested as the pretreatment option of nerve agents’ intoxications. Recently, we synthesized series of Michael’s adducts of secondary monocyclic amineson aroylacrylic acid phenylamides. These compounds showed low micromolar activity toward both acetyl- and butyrylcholinesterase. In the present work we aimed to improve the inhibitory activity toward both enzymes and redesigned the basic structural scaffold by synthesizing novel series of aroylacrylic acid phenylamide derivatives by using three suitable Michael's acceptors: 1-benzyl-4-piperidinamine, 4-benzylpiperidine and N,N-dimethyl-N-[2-(1-piperazinyl)ethyl]amine. Fifteen derivatives were synthesized with variation of substituents on aroyl- and phenylamide rings. The compounds were characterized by ¹H and ¹³C NMR spectroscopy and the easiness of Michael's addition in relation to the structure of the amine used was analysed.

Keywords: Acetylcholinesterase, aroylacrylic acid derivatives, Michael's addition, NMR spectroscopy