Bridged 5,6,7,8-Tetrahydro-1,6-naphthyridines, Analogues of Huperzine A: Synthesis, Modelling Studies and Evaluation as Inhibitors of Acetylcholinesterase

摘要: Derivatives of 6,8-bridged 5,6,7,8-tetrahydro-1,6-naphthyridines, designed as analogues huperzine A, were synthesised and evaluated inhibitors acetylcholinesterase. In a first approach, C3-bridged naphthyridines constructed by internal nucleophilic aromatic substitution 2-chloro-3-(1-piperidinylmethyl)pyridine precursors containing 3-CO2Me group on the 1-piperidinyl ring moiety. Alternatively, ring-closing metathesis 6,8-diallyl-substituted tetrahydro-1,6-naphthyridines was applied to construct an unsaturated C4 bridge. Some target compounds showed inhibition acetylcholinesterase but lower than that A. The relative order activities could be rationalised comparative docking simulation studies basis known crystal structure acetylcholinesterase–huperzine A complex.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)