Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors
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....
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ftutrentoiris:oai:iris.unitn.it:11572/408035 2024-09-15T17:47:01+00:00 Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors Defant, Andrea Carloni, Giacomo Innocenti, Nicole Trobec, Tomaž Frangež, Robert Sepčić, Kristina Mancini, Ines Defant, Andrea Carloni, Giacomo Innocenti, Nicole Trobec, Tomaž Frangež, Robert Sepčić, Kristina Mancini, Ines 2024 ELETTRONICO https://hdl.handle.net/11572/408035 https://doi.org/10.3390/md22040173 eng eng country:CHE info:eu-repo/semantics/altIdentifier/wos/WOS:001210524000001 volume:2024/22 issue:4 firstpage:173 lastpage:187 numberofpages:15 journal:MARINE DRUGS https://hdl.handle.net/11572/408035 doi:10.3390/md22040173 info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85191505625 info:eu-repo/semantics/openAccess marine metabolite drug design organic synthesi molecular docking ADME prediction acetylcholinesterase inhibition Alzheimer’s disease info:eu-repo/semantics/article 2024 ftutrentoiris https://doi.org/10.3390/md22040173 2024-07-01T23:39:19Z 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. Article in Journal/Newspaper Antarc* Antarctic Università degli Studi di Trento: CINECA IRIS Marine Drugs 22 4 173 |
institution |
Open Polar |
collection |
Università degli Studi di Trento: CINECA IRIS |
op_collection_id |
ftutrentoiris |
language |
English |
topic |
marine metabolite drug design organic synthesi molecular docking ADME prediction acetylcholinesterase inhibition Alzheimer’s disease |
spellingShingle |
marine metabolite drug design organic synthesi molecular docking ADME prediction acetylcholinesterase inhibition Alzheimer’s disease Defant, Andrea Carloni, Giacomo Innocenti, Nicole Trobec, Tomaž Frangež, Robert Sepčić, Kristina Mancini, Ines Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors |
topic_facet |
marine metabolite drug design organic synthesi molecular docking ADME prediction acetylcholinesterase inhibition Alzheimer’s disease |
description |
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. |
author2 |
Defant, Andrea Carloni, Giacomo Innocenti, Nicole Trobec, Tomaž Frangež, Robert Sepčić, Kristina Mancini, Ines |
format |
Article in Journal/Newspaper |
author |
Defant, Andrea Carloni, Giacomo Innocenti, Nicole Trobec, Tomaž Frangež, Robert Sepčić, Kristina Mancini, Ines |
author_facet |
Defant, Andrea Carloni, Giacomo Innocenti, Nicole Trobec, Tomaž Frangež, Robert Sepčić, Kristina Mancini, Ines |
author_sort |
Defant, Andrea |
title |
Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors |
title_short |
Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors |
title_full |
Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors |
title_fullStr |
Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors |
title_full_unstemmed |
Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors |
title_sort |
structural insights into the marine alkaloid discorhabdin g as a scaffold towards new acetylcholinesterase inhibitors |
publisher |
country:CHE |
publishDate |
2024 |
url |
https://hdl.handle.net/11572/408035 https://doi.org/10.3390/md22040173 |
genre |
Antarc* Antarctic |
genre_facet |
Antarc* Antarctic |
op_relation |
info:eu-repo/semantics/altIdentifier/wos/WOS:001210524000001 volume:2024/22 issue:4 firstpage:173 lastpage:187 numberofpages:15 journal:MARINE DRUGS https://hdl.handle.net/11572/408035 doi:10.3390/md22040173 info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85191505625 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/10.3390/md22040173 |
container_title |
Marine Drugs |
container_volume |
22 |
container_issue |
4 |
container_start_page |
173 |
_version_ |
1810495505871929344 |