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The proposed two-step reaction sequence had a high experimentally confirmed synthetic success rate (up to 85%) and gave reasonable product yields (up to 61%). As a result of the validation process, a 262-member compound library (out of &gt;70K accessible combinations) was prepared. Biological profiling of the synthesized library by differential scanning fluorimetry and enzymatic assays identified several low micromolar inhibitors of human carbonic anhydrase. The interaction of the discovered hits with the biological target was studied by docking and molecular dynamics.<\/jats:p>","DOI":"10.3390\/molecules31020318","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T14:46:33Z","timestamp":1768574793000},"page":"318","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Click Chemistry-Enabled Parallel Synthesis of N-Acyl Sulfonamides and Their Evaluation as Carbonic Anhydrase Inhibitors"],"prefix":"10.3390","volume":"31","author":[{"given":"Oleksii V.","family":"Gavrylenko","sequence":"first","affiliation":[{"name":"Enamine Ltd., Winston Churchill Street 78, 02094 Ky\u0457v, Ukraine"},{"name":"V. P. 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Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Akademik Kukhar Street 1, 02066 Ky\u0457v, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1179-2993","authenticated-orcid":false,"given":"Sergey A.","family":"Zozulya","sequence":"additional","affiliation":[{"name":"Enamine Biology (Bienta)\/Enamine Ltd., Winston Churchill Street 78, 02094 Ky\u0457v, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5444-7754","authenticated-orcid":false,"given":"Dmytro S.","family":"Radchenko","sequence":"additional","affiliation":[{"name":"Enamine Ltd., Winston Churchill Street 78, 02094 Ky\u0457v, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6036-5859","authenticated-orcid":false,"given":"Oleksandr O.","family":"Grygorenko","sequence":"additional","affiliation":[{"name":"Enamine Ltd., Winston Churchill Street 78, 02094 Ky\u0457v, Ukraine"},{"name":"Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601 Ky\u0457v, Ukraine"},{"name":"Enamine Scientific Research Institute, Winston Churchill Street 67, 02094 Ky\u0457v, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6073-002X","authenticated-orcid":false,"given":"Yurii S.","family":"Moroz","sequence":"additional","affiliation":[{"name":"Enamine Ltd., Winston Churchill Street 78, 02094 Ky\u0457v, Ukraine"},{"name":"Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601 Ky\u0457v, Ukraine"},{"name":"Chemspace LLC, Winston Churchill Street 85, 02094 Ky\u0457v, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A Major Update to the DrugBank Database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1111\/cbdd.13043","article-title":"N-Acylsulfonamides: Synthetic Routes and Biological Potential in Medicinal Chemistry","volume":"90","author":"Ammazzalorso","year":"2017","journal-title":"Chem. 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Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1002\/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4","article-title":"A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective \u201cLigation\u201d of Azides and Terminal Alkynes","volume":"41","author":"Rostovtsev","year":"2002","journal-title":"Angew. Chemie Int. Ed."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1039\/b904091a","article-title":"Copper-Catalyzed Azide\u2013Alkyne Cycloaddition (CuAAC) and beyond: New Reactivity of Copper(i) Acetylides","volume":"39","author":"Hein","year":"2010","journal-title":"Chem. Soc. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9528","DOI":"10.1039\/C5OB01457C","article-title":"Copper-Catalysed Azide\u2013Alkyne Cycloadditions (CuAAC): An Update","volume":"13","author":"Nicasio","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1021\/cr0783479","article-title":"Cu-Catalyzed Azide\u2212Alkyne Cycloaddition","volume":"108","author":"Meldal","year":"2008","journal-title":"Chem. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.drudis.2015.08.004","article-title":"Discovery of Bioactive Molecules from CuAAC Click-Chemistry-Based Combinatorial Libraries","volume":"21","author":"Wang","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1021\/acscombsci.5b00087","article-title":"CuAAC: An Efficient Click Chemistry Reaction on Solid Phase","volume":"18","author":"Castro","year":"2016","journal-title":"ACS Comb. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1039\/D4MD00469H","article-title":"Rapid Identification of Novel Indolylarylsulfone Derivatives as Potent HIV-1 NNRTIs via Miniaturized CuAAC Click-Chemistry-Based Combinatorial Libraries","volume":"16","author":"Gao","year":"2025","journal-title":"RSC Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D1388","DOI":"10.1093\/nar\/gkaa971","article-title":"PubChem in 2021: New Data Content and Improved Web Interfaces","volume":"49","author":"Kim","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D1100","DOI":"10.1093\/nar\/gkr777","article-title":"ChEMBL: A Large-Scale Bioactivity Database for Drug Discovery","volume":"40","author":"Gaulton","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3400","DOI":"10.1016\/j.bmcl.2008.04.012","article-title":"Potent Triazolyl-Proline-Based Inhibitors of HCV NS3 Protease","volume":"18","author":"Naud","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3522","DOI":"10.1021\/jm500255y","article-title":"Cyclic Secondary Sulfonamides: Unusually Good Inhibitors of Cancer-Related Carbonic Anhydrase Enzymes","volume":"57","author":"Moeker","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1021\/acsmedchemlett.7b00389","article-title":"Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors","volume":"8","author":"Sharp","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e202401307","DOI":"10.1002\/chem.202401307","article-title":"Photocatalytic Synthesis and Functionalization of Sulfones, Sulfonamides and Sulfoximines","volume":"30","author":"Rosso","year":"2024","journal-title":"Chem.\u2013A Eur. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1080\/14756366.2016.1198900","article-title":"A Class of Sulfonamides as Carbonic Anhydrase I and II Inhibitors","volume":"31","author":"Gokcen","year":"2016","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4834","DOI":"10.1021\/jm0501073","article-title":"Carbonic Anhydrase Inhibitors. Design of Fluorescent Sulfonamides as Probes of Tumor-Associated Carbonic Anhydrase IX That Inhibit Isozyme IX-Mediated Acidification of Hypoxic Tumors","volume":"48","author":"Cecchi","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"117467","DOI":"10.1016\/j.bmc.2023.117467","article-title":"Design and Synthesis of Sulfonamides Incorporating a Biotin Moiety: Carbonic Anhydrase Inhibitory Effects, Antiproliferative Activity and Molecular Modeling Studies","volume":"94","author":"Begines","year":"2023","journal-title":"Bioorg. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"133260","DOI":"10.1016\/j.molstruc.2022.133260","article-title":"Nitroimidazole-Sulfonamides as Carbonic Anhydrase IX and XII Inhibitors Targeting Tumor Hypoxia: Design, Synthesis, Molecular Docking and Molecular Dynamics Simulation","volume":"1264","author":"Almatary","year":"2022","journal-title":"J. Mol. Struct."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5293349","DOI":"10.1155\/2022\/5293349","article-title":"Synthesis, Carbonic Anhydrase II\/IX\/XII Inhibition, DFT, and Molecular Docking Studies of Hydrazide-Sulfonamide Hybrids of 4-Methylsalicyl- and Acyl-Substituted Hydrazide","volume":"2022","author":"Khushal","year":"2022","journal-title":"Biomed Res. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8767","DOI":"10.1039\/D3CP05846H","article-title":"Discovery of Non-Sulfonamide Carbonic Anhydrase IX Inhibitors through Structure-Based Virtual Screening","volume":"26","author":"Cheng","year":"2024","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"G\u00fcttler, A., Eiselt, Y., Funtan, A., Thiel, A., Petrenko, M., Ke\u00dfler, J., Thondorf, I., Paschke, R., Vordermark, D., and Bache, M. (2021). Betulin Sulfonamides as Carbonic Anhydrase Inhibitors and Anticancer Agents in Breast Cancer Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168808"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5465","DOI":"10.1016\/j.bmc.2008.04.011","article-title":"Synthesis, in Vitro Antibacterial and Carbonic Anhydrase II Inhibitory Activities of N-Acylsulfonamides Using Silica Sulfuric Acid as an Efficient Catalyst under Both Solvent-Free and Heterogeneous Conditions","volume":"16","author":"Massah","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"36139","DOI":"10.18632\/oncotarget.5684","article-title":"Sulfonamide Derivative Targeting Carbonic Anhydrase IX as a Nuclear Imaging Probe for Colorectal Cancer Detection in Vivo","volume":"6","author":"Guan","year":"2015","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1107\/S0907444910006554","article-title":"Atomic Resolution Studies of Carbonic Anhydrase II","volume":"66","author":"Behnke","year":"2010","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"26800","DOI":"10.18632\/oncotarget.25508","article-title":"Novel Fluorinated Carbonic Anhydrase IX Inhibitors Reduce Hypoxia-Induced Acidification and Clonogenic Survival of Cancer Cells","volume":"9","author":"Niemans","year":"2018","journal-title":"Oncotarget"},{"key":"ref_33","unstructured":"(2025, February 10). Available online: https:\/\/www.molsoft.com."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High Performance Molecular Simulations through Multi-Level Parallelism from Laptops to Supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"Gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS","volume":"17","author":"Valiente","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Armarego, W.L.F., and Chai, C. (2003). Purification of Laboratory Chemicals, Elsevier. [5th ed.].","DOI":"10.1016\/B978-075067571-0\/50008-9"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1021\/acs.biochem.6b00243","article-title":"The Structure of Carbonic Anhydrase IX Is Adapted for Low-PH Catalysis","volume":"55","author":"Mahon","year":"2016","journal-title":"Biochemistry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.pep.2004.06.031","article-title":"Purification of Recombinant Human Carbonic Anhydrase-II by Metal Affinity Chromatography without Incorporating Histidine Tags","volume":"37","author":"Banerjee","year":"2004","journal-title":"Protein Expr. Purif."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1177\/1087057103260050","article-title":"Determining Appropriate Substrate Conversion for Enzymatic Assays in High-Throughput Screening","volume":"8","author":"Wu","year":"2003","journal-title":"SLAS Discov."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/jcc.540150503","article-title":"ICM\u2014A New Method for Protein Modeling and Design: Applications to Docking and Structure Prediction from the Distorted Native Conformation","volume":"15","author":"Abagyan","year":"1994","journal-title":"J. Comput. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1006\/jmbi.1994.1052","article-title":"Biased Probability Monte Carlo Conformational Searches and Electrostatic Calculations for Peptides and Proteins","volume":"235","author":"Abagyan","year":"1994","journal-title":"J. Mol. Biol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/2\/318\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T05:13:28Z","timestamp":1768713208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/2\/318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,16]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["molecules31020318"],"URL":"https:\/\/doi.org\/10.3390\/molecules31020318","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,16]]}}}