{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T18:34:22Z","timestamp":1788978862815,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["24-15-00334"],"award-info":[{"award-number":["24-15-00334"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["GM103474"],"award-info":[{"award-number":["GM103474"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes of Health IDeA Program","award":["24-15-00334"],"award-info":[{"award-number":["24-15-00334"]}]},{"name":"National Institutes of Health IDeA Program","award":["GM103474"],"award-info":[{"award-number":["GM103474"]}]},{"name":"Montana State University Agricultural Experiment Station","award":["24-15-00334"],"award-info":[{"award-number":["24-15-00334"]}]},{"name":"Montana State University Agricultural Experiment Station","award":["GM103474"],"award-info":[{"award-number":["GM103474"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Oximes have been reported to exhibit useful pharmaceutical properties, including compounds with anticancer, anti-arthritis, antibacterial, and neuroprotective activities. Many oximes are kinase inhibitors and have been shown to inhibit various kinases. Herein, a panel of oxime derivatives of tricyclic isatins was synthesized and evaluated for inhibition of cellular inflammatory responses and binding affinity to several kinases. Compounds 5a and 5d (a.k.a. NS-102), which have an unsubstituted oxime group, inhibited lipopolysaccharide (LPS)-induced nuclear factor-\u03baB\/activating protein 1 (NF-\u03baB\/AP-1) transcriptional activity in human THP-1Blue monocytic cells and interleukin-6 (IL-6) production in human MonoMac-6 monocytic cells, with IC50 values in the micromolar range. These compounds also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1\u03b1, IL-1\u03b2, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Compounds 5a and 5d exhibited nanomolar\/submicromolar binding affinity toward several kinase targets. The most potent inhibitor, 5d (3-(hydroxyimino)-5-nitro-1,3,6,7,8,9-hexahydro-2H-benzo[g]indol-2-one), demonstrated high binding affinity for 12 kinases, including DYRK1A, DYRK1B, PIM1, Haspin, HIPK1-3, IRAK1, NEK10, and DAPK1-3. Molecular modeling suggested modes of binding interaction of selected compounds in the DYRK1A and PIM1 catalytic sites that agreed with the experimental binding data. Our results demonstrate that tricyclic isatin oximes could be potential candidates for developing anti-inflammatory drugs with neuroprotective effects for treating neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/molecules30142914","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T09:38:27Z","timestamp":1752140307000},"page":"2914","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tricyclic Isatin Derivatives as Anti-Inflammatory Compounds with High Kinase Binding Affinity"],"prefix":"10.3390","volume":"30","author":[{"given":"Alexander V.","family":"Uvarov","sequence":"first","affiliation":[{"name":"Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor A.","family":"Schepetkin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8114-5073","authenticated-orcid":false,"given":"Mark T.","family":"Quinn","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3022-4510","authenticated-orcid":false,"given":"Andrei I.","family":"Khlebnikov","sequence":"additional","affiliation":[{"name":"Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Frost, D., Meechoovet, B., Wang, T., Gately, S., Giorgetti, M., Shcherbakova, I., and Dunckley, T. (2011). Carboline Compounds, Including Harmine, Inhibit DYRK1A and Tau Phosphorylation at Multiple Alzheimer\u2019s Disease-Related Sites. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019264"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Latosi\u0144ska, M., and Latosi\u0144ska, J.N. (2024). Serine\/Threonine Protein Kinases as Attractive Targets for Anti-Cancer Drugs\u2014An Innovative Approach to Ligand Tuning Using Combined Quantum Chemical Calculations, Molecular Docking, Molecular Dynamic Simulations, and Network-like Similarity Graphs. Molecules, 29.","DOI":"10.3390\/molecules29133199"},{"key":"ref_3","first-page":"136","article-title":"The PIM family of serine\/threonine kinases in cancer","volume":"34","author":"Carnero","year":"2013","journal-title":"Med. Res. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"110303","DOI":"10.1016\/j.cellsig.2022.110303","article-title":"Roles and regulation of Haspin kinase and its impact on carcinogenesis","volume":"93","author":"Quadri","year":"2022","journal-title":"Cell. Signal."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nishida-Fukuda, H., Tokuhiro, K., Ando, Y., Matsushita, H., Wada, M., and Tanaka, H. (2021). Evaluation of the antiproliferative effects of the HASPIN inhibitor CHR-6494 in breast cancer cell lines. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0249912"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lin, C.-I., Chen, Z.-C., Chen, C.-H., Chang, Y.-H., Lee, T.-C., Tang, T.-T., Yang, C.-M., Tsai, M.-C., Huang, C.-C., and Yang, T.-W. (2022). Co-inhibition of Aurora A and Haspin kinases enhances survivin blockage and p53 induction for mitotic catastrophe and apoptosis in human colorectal cancer. Biochem. Pharmacol., 206.","DOI":"10.1016\/j.bcp.2022.115289"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ananthapadmanabhan, V., Shows, K.H., Dickinson, A.J., and Litovchick, L. (2023). Insights from the protein interaction Universe of the multifunctional Goldilocks kinase DYRK1A. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1277537"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/hmg\/ddl437","article-title":"The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between-amyloid production and tau phosphorylation in Alzheimer disease","volume":"16","author":"Kimura","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s00401-008-0419-6","article-title":"The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome","volume":"116","author":"Wegiel","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10941","DOI":"10.1007\/s12035-024-04257-7","article-title":"Role of PIM Kinase Inhibitor in the Treatment of Alzheimers Disease","volume":"61","author":"Meur","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tanaka, H., Matsushita, H., Tokuhiro, K., Fukunari, A., and Ando, Y. (2023). Ingestion of soybean sprouts containing a HASPIN in-hibitor improves condition in a mouse model of Alzheimer\u2019s disease. Biology, 12.","DOI":"10.3390\/biology12020320"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s12020-023-03362-2","article-title":"Metabolic adverse events of multitarget kinase inhibitors: A systematic review","volume":"81","author":"Acitelli","year":"2023","journal-title":"Endocrine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"116016","DOI":"10.1016\/j.ejmech.2023.116016","article-title":"Targeting PIM kinases in cancer therapy: An update on pharmacological small-molecule inhibitors","volume":"264","author":"Chen","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1007\/s00011-024-01924-2","article-title":"The role of Pim-1 kinases in inflammatory signaling pathways","volume":"73","author":"Baek","year":"2024","journal-title":"Inflamm. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yang, Y., Fan, X., Liu, Y., Ye, D., Liu, C., Yang, H., Su, Z., Zhang, Y., and Liu, Y. (2023). Function and inhibition of DYRK1A: Emerging roles of treating multiple human diseases. Biochem. Pharmacol., 212.","DOI":"10.1016\/j.bcp.2023.115521"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10346","DOI":"10.1021\/acs.jmedchem.5c00512","article-title":"AI-driven de novo design and development of nontoxic DYRK1A inhibitors","volume":"68","author":"Varas","year":"2025","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.2174\/0929867324666170414155520","article-title":"Structure, roles and inhibitors of a mitotic protein kinase Haspin","volume":"24","author":"Kestav","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/nm.4306","article-title":"The Drug Repurposing Hub: A next-generation drug library and information resource","volume":"23","author":"Corsello","year":"2017","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1126\/science.1158140","article-title":"Drug target identification using side-effect similarity","volume":"321","author":"Campillos","year":"2008","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Schepetkin, I.A., Karpenko, O.S., Kovrizhina, A.R., Kirpotina, L.N., Khlebnikov, A.I., Chekal, S.I., Radudik, A.V., Shybinska, M.O., and Quinn, M.T. (2023). Novel tryptanthrin derivatives with selectivity as c-Jun N-terminal kinase (JNK) 3 inhibitors. Molecules, 28.","DOI":"10.3390\/molecules28124806"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Schepetkin, I.A., Kovrizhina, A.R., Stankevich, K.S., Khlebnikov, A.I., Kirpotina, L.N., Quinn, M.T., and Cook, M.J. (2022). Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.958687"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ejmech.2018.10.023","article-title":"Synthesis, biological evaluation, and molecular modeling of 11H-indeno-1, 2b-quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors","volume":"161","author":"Schepetkin","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Nie, Z., Xia, X., Zhao, Y., Zhang, S., Zhang, Y., and Wang, J. (2021). JNK selective inhibitor, IQ-1S, protects the mice against lipopolysaccharides-induced sepsis. Bioorganic Med. Chem., 30.","DOI":"10.1016\/j.bmc.2020.115945"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6257","DOI":"10.1016\/j.bmc.2009.07.051","article-title":"Synthesis and kinase inhibitory activity of novel substituted indigoids","volume":"17","author":"Beauchard","year":"2009","journal-title":"Bioorganic Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Schepetkin, I.A., Plotnikov, M.B., Khlebnikov, A.I., Plotnikova, T.M., and Quinn, M.T. (2021). Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential. Biomolecules, 11.","DOI":"10.3390\/biom11060777"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1039\/c3np20118j","article-title":"Simple indole alkaloids and those with a non-rearranged monoterpenoid unit","volume":"30","author":"Ishikura","year":"2013","journal-title":"Nat. Prod. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Cap\u00f3, T., Rebassa, J.B., Ra\u00efch, I., Lillo, J., Badia, P., Navarro, G., and Reyes-Resina, I. (2025). Future perspectives of NMDAR in CNS disorders. Molecules, 30.","DOI":"10.3390\/molecules30040877"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2","DOI":"10.2174\/0109298665348075241121071614","article-title":"Exploring New Structures of Kinase Inhibitors and Multitarget Strategies in Alzheimer\u2019s Disease Treatment","volume":"32","author":"Tripathi","year":"2025","journal-title":"Protein Pept. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s00726-001-0107-5","article-title":"Domoic acid neurotoxicity in hippocampal slice cultures","volume":"23","author":"Jakobsen","year":"2002","journal-title":"Amino Acids"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1139\/y96-110","article-title":"Selective reduction in domoic acid toxicity in vivo by a novel non-N-methyl-D-aspartate receptor antagonist","volume":"74","author":"Tasker","year":"1996","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1007\/s12264-020-00594-4","article-title":"Connexin 36 mediates orofacial pain hypersensitivity through GluK2 and TRPA1","volume":"36","author":"Li","year":"2020","journal-title":"Neurosci. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/S0306-4522(98)00573-9","article-title":"A high-affinity presynaptic kainate-type glutamate receptor facilitates glutamate exocytosis from cerebral cortex nerve terminals (synaptosomes)","volume":"90","author":"Perkinton","year":"1999","journal-title":"Neuroscience"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1111\/j.1469-7793.1998.833bm.x","article-title":"Kainate receptor-mediated inhibition of presynaptic Ca2+ influx and EPSP in area CA1 of the rat hippocampus","volume":"509","author":"Kamiya","year":"1998","journal-title":"J. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/cns.12487","article-title":"NS383 Selectively Inhibits Acid-Sensing Ion Channels Containing 1a and 3 Subunits to Reverse Inflammatory and Neuropathic Hyperalgesia in Rats","volume":"22","author":"Munro","year":"2015","journal-title":"Cns Neurosci. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sun, A.W., Wu, M.H., Vijayalingam, M., Wacker, M.J., and Chu, X.-P. (2023). The role of zinc in modulating acid-sensing ion channel function. Biomolecules, 13.","DOI":"10.3390\/biom13020229"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0960-894X(00)80101-8","article-title":"Isatin oximes-A novel series of bioavailable non-NMDA antagonists","volume":"3","author":"Nielsen","year":"1993","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_37","first-page":"193","article-title":"Synthesis, reaction and biological importance of isatin derivatives","volume":"1","author":"Fahad","year":"2022","journal-title":"Biomed. Chem. Sci."},{"key":"ref_38","unstructured":"Zhungietu, G.I., and Rechter, M.A. (1977). Isatin and Its Derivatives, Academy of Sciences of the Moldavian SSR, Institute of Chemistry. (In Russian)."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1021\/cr50020a004","article-title":"Polyphosphoric acids as a reagent in organic chemistry","volume":"58","author":"Popp","year":"1958","journal-title":"Chem. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1021\/jo01135a015","article-title":"An antimalarial alkaloid from hydrangea. XV. Synthesis of 5-, 6-, 7-, and 8-derivatives with two identical substituents","volume":"17","author":"Baker","year":"1952","journal-title":"J. Org. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1007\/BF00472618","article-title":"Mononitration of derivatives of benzisatins","volume":"25","author":"Mazhilis","year":"1989","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1046\/j.1440-1711.2001.01025.x","article-title":"Cross-talk between pro-inflammatory transcription factors and glucocorticoids","volume":"79","author":"Adcock","year":"2001","journal-title":"Immunol. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nbt1358","article-title":"A quantitative analysis of kinase inhibitor selectivity","volume":"26","author":"Karaman","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nbt1068","article-title":"A small molecule-kinase interaction map for clinical kinase inhibitors","volume":"23","author":"Fabian","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8470","DOI":"10.1074\/jbc.RA119.012365","article-title":"The protein kinase MAP3K19 phosphorylates MAP2Ks and thereby activates ERK and JNK kinases and increases viability of KRAS-mutant lung cancer cells","volume":"295","author":"Hoang","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/ncomms1090","article-title":"Development of a novel selective inhibitor of the Down syndrome-related kinase DYRK1A","volume":"1","author":"Ogawa","year":"2010","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4434","DOI":"10.1016\/j.bmc.2015.06.018","article-title":"Design and synthesis of a potent inhibitor of class 1 DYRK kinases as a suppressor of adipogenesis","volume":"23","author":"Masaki","year":"2015","journal-title":"Bioorganic Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1016\/j.bmcl.2006.12.086","article-title":"Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase","volume":"17","author":"Cheney","year":"2007","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1021\/ml300207a","article-title":"Novel inverse binding mode of indirubin derivatives yields improved selectivity for DYRK kinases","volume":"4","author":"Myrianthopoulos","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Lyskov, S., Chou, F.-C., Conch\u00fair, S., Der, B.S., Drew, K., Kuroda, D., Xu, J., Weitzner, B.D., Renfrew, P.D., and Sripakdeevong, P. (2013). Serverification of molecular modeling applications: The Rosetta Online Server that Includes Everyone (ROSIE). PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063906"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"DeLuca, S., Khar, K., and Meiler, J. (2015). Fully flexible docking of medium sized ligand libraries with Rosetta ligand. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132508"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1038\/nprot.2013.074","article-title":"Small-molecule ligand docking into comparative models with Rosetta","volume":"8","author":"Combs","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13321-015-0095-1","article-title":"BCL::CONF: Small molecule conformational sampling using a knowledge based rotamer library","volume":"7","author":"Kothiwale","year":"2015","journal-title":"J. Cheminform."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/14\/2914\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:07:41Z","timestamp":1760033261000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/14\/2914"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,10]]},"references-count":53,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["molecules30142914"],"URL":"https:\/\/doi.org\/10.3390\/molecules30142914","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,10]]}}}