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

Abstract Derivatives of 6,8‐bridged 5,6,7,8‐tetrahydro‐1,6‐naphthyridines, designed as analogues of huperzine A, were synthesised and evaluated as inhibitors of acetylcholinesterase. In a first approach, C 3 ‐bridged naphthyridines were constructed by internal nucleophilic aromatic substitution of 2‐chloro‐3‐(1‐piperidinylmethyl)pyridine precursors containing a 3‐CO 2 Me group on the 1‐piperidinyl ring moiety. Alternatively, ring‐closing metathesis on 6,8‐diallyl‐substituted tetrahydro‐1,6‐naphthyridines was applied to construct an unsaturated C 4 bridge. Some of the target compounds showed inhibition of acetylcholinesterase but lower than that of huperzine A. The relative order of inhibition activities could be rationalised by comparative docking simulation studies on the basis of the known crystal structure of the acetylcholinesterase–huperzine A complex.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)