Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors

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dc.authoridGambacorta, Nicola/0000-0003-1965-1519
dc.authoridOzdemir, Zenyep/0000-0003-4559-2305
dc.authoridBuyuktuncel, Ebru/0000-0001-7269-6594
dc.authoridNicolotti, Orazio/0000-0001-6533-5539
dc.authoridKim, Hoon/0000-0002-7203-3712
dc.authoridabdelgawad, mohamed/0000-0001-9035-5638
dc.authorwosidAbdelgawad, Mohamed A./X-5943-2019
dc.authorwosidMusa, Arafa/KHE-0736-2024
dc.authorwosidBuyuktuncel, Saliha Ebru/ABH-9343-2020
dc.authorwosidGambacorta, Nicola/ACW-4658-2022
dc.authorwosidOzdemir, Zenyep/AAJ-6384-2020
dc.authorwosidNicolotti, Orazio/F-3209-2012
dc.contributor.authorCecen, Muhammed
dc.contributor.authorOh, Jong Min
dc.contributor.authorOzdemir, Zeynep
dc.contributor.authorBuyuktuncel, Saliha Ebru
dc.contributor.authorUysal, Mehtap
dc.contributor.authorAbdelgawad, Mohamed A.
dc.contributor.authorMusa, Arafa
dc.date.accessioned2024-08-04T20:49:05Z
dc.date.available2024-08-04T20:49:05Z
dc.date.issued2020
dc.departmentİnönü Üniversitesien_US
dc.description.abstractTwelve pyridazinones (T1-T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 mu M, followed by T3 (IC50 = 0.039 mu M). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH3)(2) (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57 and 4.19 mu M and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with K-i values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer's disease.en_US
dc.description.sponsorshipNational Research Foundation of Korea (NRF) - Republic of Korea government [NRF-2019R1A2C1088967]en_US
dc.description.sponsorshipThis research was supported by the National Research Foundation of Korea (NRF) grant funded by the Republic of Korea government (NRF-2019R1A2C1088967) (to H.K.).en_US
dc.identifier.doi10.3390/molecules25225371
dc.identifier.issn1420-3049
dc.identifier.issue22en_US
dc.identifier.pmid33212876en_US
dc.identifier.scopus2-s2.0-85096458380en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.3390/molecules25225371
dc.identifier.urihttps://hdl.handle.net/11616/99639
dc.identifier.volume25en_US
dc.identifier.wosWOS:000594096400001en_US
dc.identifier.wosqualityQ2en_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 oxidaseen_US
dc.subjectpyridazinoneen_US
dc.subjectkineticsen_US
dc.subjectreversibilityen_US
dc.subjectADMEen_US
dc.subjectmolecular dockingen_US
dc.titleDesign, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitorsen_US
dc.typeArticleen_US

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