Repurposing of 8-Hydroxyquinoline-Based Butyrylcholinesterase and Cathepsin B Ligands as Potent Nonpeptidic Deoxyribonuclease I Inhibitors

Autor: Mihajlo Gajic, Damijan Knez, Izidor Sosič, Janez Mravljak, Anže Meden, Urban Košak, Luisa Leitzbach, Sven George, Bettina Hofmann, Aleksandra Zivkovic, Dieter Steinhilber, Holger Stark, Stanislav Gobec, Andrija Smelcerovic, Marko Anderluh
Rok vydání: 2021
Předmět:
Zdroj: ChemMedChem, str. 1-11, Vol. 17, iss. 5, 2022
COBISS-ID: 519053337
ISSN: 1860-7187
Popis: 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 up to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35 µM and 50 nM, respectively, while 2 nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 µM and 20 µM, respectively. 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. Nasl. z nasl. zaslona. Opis vira z dne 10. 1. 2022. Št. članka: e2021006. Bibliografija: str. 10-11. Abstract. Fund of the Republic of Serbia ARRS
Databáze: OpenAIRE
Externí odkaz: