Pyridazinones and Structurally Related Derivatives with Anti-Inflammatory Activity

dc.contributor.authorCantini, Niccolo
dc.contributor.authorSchepetkin, Igor A.
dc.contributor.authorDanilenko, Nadezhda V.
dc.contributor.authorKhlebnikov, Andrei I.
dc.contributor.authorCrocetti, Letizia
dc.contributor.authorGiovannoni, Maria Paola
dc.contributor.authorKirpotina, Liliya N.
dc.contributor.authorQuinn, Mark T.
dc.date.accessioned2022-11-07T18:14:51Z
dc.date.available2022-11-07T18:14:51Z
dc.date.issued2022-06
dc.description.abstractPersistent inflammation contributes to a number of diseases; therefore, control of the inflammatory response is an important therapeutic goal. In an effort to identify novel anti-inflammatory compounds, we screened a library of pyridazinones and structurally related derivatives that were used previously to identify N-formyl peptide receptor (FPR) agonists. Screening of the compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP1-Blue monocytic cells identified 48 compounds with anti-inflammatory activity. Interestingly, 34 compounds were FPR agonists, whereas 14 inhibitors of LPS-induced NF-κB activity were not FPR agonists, indicating that they inhibited different signaling pathways. Further analysis of the most potent inhibitors showed that they also inhibited LPS-induced production of interleukin 6 (IL-6) by human MonoMac-6 monocytic cells, again verifying their anti-inflammatory properties. Structure–activity relationship (SAR) classification models based on atom pair descriptors and physicochemical ADME parameters were developed to achieve better insight into the relationships between chemical structures of the compounds and their biological activities, and we found that there was little correlation between FPR agonist activity and inhibition of LPS-induced NF-κB activity. Indeed, Cmpd43, a well-known pyrazolone-based FPR agonist, as well as FPR1 and FPR2 peptide agonists had no effect on the LPS-induced NF-κB activity in THP1-Blue cells. Thus, some FPR agonists reported to have anti-inflammatory activity may actually mediate their effects through FPR-independent pathways, as it is suggested by our results with this series of compounds. This could explain how treatment with some agonists known to be inflammatory (i.e., FPR1 agonists) could result in anti-inflammatory effects. Further research is clearly needed to define the molecular targets of pyridazinones and structurally related compounds with anti-inflammatory activity and to define their relationships (if any) to FPR signaling events.en_US
dc.identifier.citationCantini, N.; Schepetkin, I.A.; Danilenko, N.V.; Khlebnikov, A.I.; Crocetti, L.; Giovannoni, M.P.; Kirpotina, L.N.; Quinn, M.T. Pyridazinones and Structurally Related Derivatives with Anti-Inflammatory Activity. Molecules 2022, 27, 3749. https:// doi.org/10.3390/molecules27123749en_US
dc.identifier.issn1420-3049
dc.identifier.urihttps://scholarworks.montana.edu/handle/1/17347
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.rightscc-byen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectanti-inflammatoryen_US
dc.subjectpyridazinoneen_US
dc.subjectN-Formyl peptid receptoren_US
dc.subjectnuclear factor-κBen_US
dc.subjectmonocyte/ macrophageen_US
dc.subjectbinary classification treeen_US
dc.titlePyridazinones and Structurally Related Derivatives with Anti-Inflammatory Activityen_US
dc.typeArticleen_US
mus.citation.extentfirstpage1en_US
mus.citation.extentlastpage27en_US
mus.citation.issue12en_US
mus.citation.journaltitleMoleculesen_US
mus.citation.volume27en_US
mus.identifier.doi10.3390/molecules27123749en_US
mus.relation.collegeCollege of Agricultureen_US
mus.relation.departmentMicrobiology & Immunology.en_US
mus.relation.universityMontana State University - Bozemanen_US

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