Inhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivatives

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dc.authoridKim, Hoon/0000-0002-7203-3712
dc.contributor.authorOh, Jong Min
dc.contributor.authorZenni, Yaren Nur
dc.contributor.authorOzdemir, Zeynep
dc.contributor.authorKumar, Sunil
dc.contributor.authorKilic, Semanur
dc.contributor.authorAkdag, Mevlut
dc.contributor.authorOzcelik, Azime Berna
dc.date.accessioned2024-08-04T20:56:12Z
dc.date.available2024-08-04T20:56:12Z
dc.date.issued2024
dc.departmentİnönü Üniversitesien_US
dc.description.abstractMonoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson's disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 mu M, followed by S16 (IC50 = 0.979 mu M). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 mu M, followed by S5 (IC50 = 3.857 mu M). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH3 > -F > -CN > -CH3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the K-i values of S5 and S16 for MAO-B were 0.155 +/- 0.050 and 0.721 +/- 0.074 mu M, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood-brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi-pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.en_US
dc.description.sponsorshipResearch Foundation of Inonu University,Inonu University, Malatya, Turkiye [TYL-2023-3186]en_US
dc.description.sponsorshipThis study was supported by the Research Foundation of Inonu University (TYL-2023-3186),Inonu University, Malatya, Turkiye.en_US
dc.identifier.doi10.3390/molecules29133097
dc.identifier.issn1420-3049
dc.identifier.issue13en_US
dc.identifier.pmid38999047en_US
dc.identifier.scopus2-s2.0-85198497272en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.3390/molecules29133097
dc.identifier.urihttps://hdl.handle.net/11616/102120
dc.identifier.volume29en_US
dc.identifier.wosWOS:001266758300001en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMdpien_US
dc.relation.ispartofMoleculesen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectmonoamine oxidase inhibitorsen_US
dc.subjectpyridazinoneen_US
dc.subjectbenzylpiperidineen_US
dc.subjectmolecular dockingen_US
dc.titleInhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivativesen_US
dc.typeArticleen_US

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