Effective Cross-Coupling Synthesis of Novel Ethynyl-Decorated Benzo[b][1,6]naphthyridines and Their Evaluation as Inhibitors of Cholinesterases and Monoamine Oxidases.

Authors

Larisa N Kulikova, Caterina Deruvo, Anna V Listratova, Raesi Gh Reza, Ekaterina S Iurina, Modesto de Candia, Nicola Gambacorta, Orazio Nicolotti, Leonid G Voskressensky, Cosimo D Altomare

Published in

Archiv der Pharmazie. Volume 359. Issue 11.

Abstract

An effective oxidative ethynylation of 1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines (THBNs) was developed. A practical improvement was achieved by optimizing a co-catalytic system composed of O₂, CuI, and DMAP. The co-catalytic system allows a decrease in the loading amount of DIAD, simplifies product isolation workup and increases the yields. The co-catalytic system proved to be effective not only with DIAD but also with the reduced forms of DIAD-H₂. Supported by predictions of in-house developed ligand-based target fishing computational tools, a series of newly synthesized 1-phenylethynyl-substituted THBN derivatives were evaluated against both human cholinesterases (AChE, BChE), and monoamine oxidases (MAOs A and B) as well. Most 1-phenylethynyl-substituted THBNs, and the respective 1-unsubstituted derivatives, inhibited AChE and BChE at single-digit micromolar concentrations (IC₅₀ = 3-10 µM). Molecular docking simulations suggested that the ethynyl substituent may engage additional hydrophobic/π-π interactions in the AChE binding sites. Notably, 12-chloro-1,2,3,4-tetrahydro-2-methylnaphtho[2,3-b][1,6]naphthyridine (3a) proved to be also a potent and selective MAO A inhibitor (IC₅₀ = 0.237 µM, selectivity index > 40).

PMID:
42956273
Bibliographic data and abstract were imported from PubMed on 30 Oct 2026.

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