Inhibition of cholinesterase activity by fluorine-containing derivatives of α-aminoalkylphosphonic acids

V. V. Kuusk, I. V. Morozova, R. S. Agabekyan, A. Yu. Aksinenko, T. A. Epishina, V. B. Sokolov, N. V. Kovaleva, A. N. Razdolsky, V. I. Fetisov, I. V. Martynov

Institute of Physiologically Active Substances, Academy of Sciences of the USSR, Chernogolovka, Moscow Region

Abstract: A series of O,O-diethyl-l-(N-α-hydrohexafluoroisobutyryl) aminoalkylphosphonates (APh) has been synthesized and their interaction with human erythrocyte acetylcholinesterase (AChE) and with horse serum butyrylcholinesterase (BuChE) studied. Most of the APhs inactivated the cholinesterases irreversible through formation of the enzyme-inhibitor intermediate. The inactivation rate constants and the enzyme-inhibitor intermediate dissociation constants are calculated. The quantitative structure-activity relationships including both hydrophobic and calculated striec parameters of substituents are developed for APh ChE interactions. Molecular mechanics (programme MM2) was used for determining strict parameters (ES). On the basis of QSAR models analysis it was concluded that hydrophobic interactions play an essential role in APh AChE binding, whereas for APh BuChE binding strict interactions are essential. Presence of at least two APh binding centres on the surface of AChE and BuChE is suggested.

Russian Journal of Bioorganic Chemistry 1990, 16 (11):1500-1508

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