{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:11:30Z","timestamp":1787026290889,"version":"build-2736575974"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>3-Alkynyl-6-aryl-isothiazolo[4,3-b]pyridines have previously been shown to be potent inhibitors of the lipid kinase FYVE finger-containing phosphoinositide kinase (PIKfyve), displaying broad-spectrum antiviral activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To further study their structure\u2013activity relationship (SAR), an efficient synthesis toward 3- bromo-5-chloro-isothiazolo[4,3-b]pyridine was established. It allowed to introduce structural modifications at positions 3 and 5 by palladium-catalyzed cross-coupling reactions and nucleophilic aromatic substitutions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and discussion<\/jats:title>\n                    <jats:p>It led to the generation of a focused library of 3,5-disubstituted isothiazolo[4,3-b]pyridines. Several derivatives exhibited potent PIKfyve inhibition (in the low nM range) in a biochemical assay and antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (in the low \u03bcM range). To gain an insight in their binding mode, molecular modeling was applied, indicating that these 3,5- disubstituted isothiazolo[4,3-b]pyridines bind to the ATP-binding site of PIKfyve, although with a different binding mode from that of the 3,6- disubstituted isothiazolo[4,3-b]pyridines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fchem.2026.1777981","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:50:47Z","timestamp":1778219447000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis, structure\u2013activity relationships, and SARS-CoV-2 antiviral activity of 3,5-disubstituted isothiazolo[4,3-b]pyridines as PIKfyve inhibitors"],"prefix":"10.3389","volume":"14","author":[{"given":"Ling-Jie","family":"Gao","sequence":"first","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demian","family":"Kalebic","sequence":"additional","affiliation":[{"name":"Sustainable Chemistry for Metals and Molecules, Department of Chemistry, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieh Wen","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine","place":["Stanford, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aakriti","family":"Gangwal","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine","place":["Stanford, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do Hoang Nhu","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine","place":["Stanford, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jef","family":"Rozenski","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Schols","sequence":"additional","affiliation":[{"name":"Molecular, Structural and Translational Virology Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathy","family":"Froeyen","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim","family":"Dehaen","sequence":"additional","affiliation":[{"name":"Sustainable Chemistry for Metals and Molecules, Department of Chemistry, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirit","family":"Einav","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine","place":["Stanford, CA, United States"]},{"name":"Biohub","place":["San Francisco, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"De Jonghe","sequence":"additional","affiliation":[{"name":"Molecular, Structural and Translational Virology Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1042\/BCJ20220217","article-title":"How many kinases are druggable? 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