Synthesis of Isomeric 3-Benzazecines Decorated with Endocyclic Allene Moiety and Exocyclic Conjugated Double Bond and Evaluation of Their Anticholinesterase Activity

Abstract

Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6-C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R³ = CH₂OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (K_i = 4.9 μM), equipotent with the corresponding 6-phenyl derivative 3n (R³ = Ph, K_i = 4.5 μM), but 90-fold more water-soluble.

Keywords: -ylidene derivatives; 3-benzazecines; acetylcholinesterase; anti-cholinesterase activity; azacyclic allenes; butyrylcholinesterase; monoamine oxidase A and B screening.