Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors

• Published in: Marine Drugs
• Main Authors: Andrea Defant, Giacomo Carloni, Nicole Innocenti, Tomaž Trobec, Robert Frangež, Kristina Sepčić, Ines Mancini
• Format: Article in Journal/Newspaper
• Language: English
• Published: MDPI AG 2024
• Subjects: marine metabolite; drug design; organic synthesis; molecular docking; ADME prediction; acetylcholinesterase inhibition; Biology (General); QH301-705.5; Antarc*; Antarctic
• Online Access: https://doi.org/10.3390/md22040173; https://doaj.org/article/e1547d66855d4e57bae55098d2f07b44

In this study, Antarctic Latrunculia sponge-derived discorhabdin G was considered a hit for developing potential lead compounds acting as cholinesterase inhibitors. The hypothesis on the pharmacophore moiety suggested through molecular docking allowed us to simplify the structure of the metabolite. ADME prediction and drug-likeness consideration provided valuable support in selecting 5-methyl-2H-benzo[h]imidazo[1,5,4-de]quinoxalin-7(3H)-one as a candidate molecule. It was synthesized in a four-step sequence starting from 2,3-dichloronaphthalene-1,4-dione and evaluated as an inhibitor of electric eel acetylcholinesterase (eeAChE), human recombinant AChE (hAChE), and horse serum butyrylcholinesterase (BChE), together with other analogs obtained by the same synthesis. The candidate molecule showed a slightly lower inhibitory potential against eeAChE but better inhibitory activity against hAChE than discorhabdin G, with a higher selectivity for AChEs than for BChE. It acted as a reversible competitive inhibitor, as previously observed for the natural alkaloid. The findings from the in vitro assay were relatively consistent with the data available from the AutoDock Vina and Protein-Ligand ANTSystem (PLANTS) calculations.