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Repurposing of 8-Hydroxyquinoline-Based Butyrylcholinesterase and Cathepsin B Ligands as Potent Nonpeptidic Deoxyribonuclease I Inhibitors |
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| Authors: | Mihajlo Gajic Dr. Damijan Knez Dr. Izidor Sosič Prof. Janez Mravljak Anže Meden Dr. Urban Košak Luisa Leitzbach Sven George Dr. Bettina Hofmann Dr. Aleksandra Zivkovic Prof. Dieter Steinhilber Prof. Holger Stark Prof. Stanislav Gobec Prof. Andrija Smelcerovic Prof. Marko Anderluh |
| Affiliation: | 1. Department of Pharmacy, Faculty of Medicine, University of Nis, Blvd. Dr. Zorana Djindjica 81, 18000 Nis, Serbia;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia;3. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Duesseldorf, Germany;4. Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt/Main, Germany;5. Department of Chemistry, Faculty of Medicine, University of Nis, Blvd. Dr. Zorana Djindjica 81, 18000 Nis, Serbia |
| Abstract: | A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors was screened in vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22 , 8 and 7 are among the most potent synthetic non-peptide DNase I inhibitors reported to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35 μM and 50 nM, respectively, while two nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 and 20 μM. Selected derivatives were screened for various co-target binding affinities at dopamine D2 and D3, histamine H3 and H4 receptors and inhibition of 5-lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non-peptide DNase I inhibitors. The present study demonstrates that 8-hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds. |
| Keywords: | DNA DNA cleavage Deoxyribonuclease I Butyrylcholinesterase Cathepsin B |