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Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors.
Defant, Andrea; Carloni, Giacomo; Innocenti, Nicole; Trobec, Tomaz; Frangez, Robert; Sepcic, Kristina; Mancini, Ines.
Affiliation
  • Defant A; Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy.
  • Carloni G; Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy.
  • Innocenti N; Unit of Structural Microbiology, Pasteur Institute, CNRS, University of Paris City, 75015 Paris, France.
  • Trobec T; Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy.
  • Frangez R; Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, 1000 Ljubljana, Slovenia.
  • Sepcic K; Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, 1000 Ljubljana, Slovenia.
  • Mancini I; Department of Biology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana, Slovenia.
Mar Drugs ; 22(4)2024 Apr 12.
Article in En | MEDLINE | ID: mdl-38667790
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Acetylcholinesterase / Butyrylcholinesterase / Electrophorus / Cholinesterase Inhibitors / Alkaloids / Molecular Docking Simulation Limits: Animals / Humans Language: En Journal: Mar Drugs Journal subject: BIOLOGIA / FARMACOLOGIA Year: 2024 Document type: Article Affiliation country: Italy Country of publication: Switzerland

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Acetylcholinesterase / Butyrylcholinesterase / Electrophorus / Cholinesterase Inhibitors / Alkaloids / Molecular Docking Simulation Limits: Animals / Humans Language: En Journal: Mar Drugs Journal subject: BIOLOGIA / FARMACOLOGIA Year: 2024 Document type: Article Affiliation country: Italy Country of publication: Switzerland