{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:12:10Z","timestamp":1776730330447,"version":"3.51.2"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The design of multitarget drugs is a growing strategy to address complex and multifactorial diseases, and heterocycles play a major role in this approach. This review aims to critically analyze the role of heterocyclic scaffolds in the development of human carbonic anhydrase inhibitors (hCAIs), emphasizing their versatility as core chemotypes, linkers, and secondary pharmacophores. By examining advances from the last 10 years, we highlight how heterocycle-based designs contribute to modulating potency and selectivity toward hCAs, as well as to the creation of hybrid molecules with enhanced therapeutic profiles. Understanding these strategies is essential for guiding future drug discovery efforts targeting hCAs and related pathologies.<\/jats:p>","DOI":"10.3390\/ph18091387","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T05:59:51Z","timestamp":1758088791000},"page":"1387","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hybrid and Chimeric Heterocycles for the Inhibition of Carbonic Anhydrases"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6874-9419","authenticated-orcid":false,"given":"Niccol\u00f2","family":"Paoletti","sequence":"first","affiliation":[{"name":"NEUROFARBA Department, Section of Pharmaceutical Science, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0669-7481","authenticated-orcid":false,"given":"Simone","family":"Giovannuzzi","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Section of Pharmaceutical Science, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Section of Pharmaceutical Science, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/18741045-v16-e2202280","article-title":"A Review on Medicinally Important Heterocyclic Compounds","volume":"16","author":"Qadir","year":"2022","journal-title":"Open Med. Chem. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Diaconu, D., Savu, M., Ciobanu, C., Mangalagiu, V., and Mangalagiu, I.I. (2025). Current strategies in design and synthesis of antifungals hybrid and chimeric diazine derivatives. Bioorg. Med. Chem., 119.","DOI":"10.1016\/j.bmc.2025.118069"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8881","DOI":"10.1021\/acs.jmedchem.9b00017","article-title":"Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms","volume":"62","author":"Zhou","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1002\/ddr.21673","article-title":"Prospects of multitarget drug designing strategies by linking molecular docking and molecular dynamics to explore the protein-ligand recognition process","volume":"81","author":"Sivakumar","year":"2020","journal-title":"Drug Dev. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1021\/acs.jmedchem.9b01456","article-title":"Designing Chimeric Molecules for Drug Discovery by Leveraging Chemical Biology","volume":"63","author":"Borsari","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.2147\/DDDT.S257494","article-title":"Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases","volume":"14","author":"Makhoba","year":"2020","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106055","DOI":"10.1016\/j.phrs.2021.106055","article-title":"Polypharmacology: The science of multi-targeting molecules","volume":"176","author":"Kabir","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e2400073","DOI":"10.1002\/ardp.202400073","article-title":"Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review","volume":"357","author":"Bendi","year":"2024","journal-title":"Arch. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4511","DOI":"10.1016\/j.bmcl.2010.06.040","article-title":"Coumarins incorporating hydroxy- and chloro-moieties selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II","volume":"20","author":"Maresca","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Supuran, C.T. (2023). A simple yet multifaceted 90 years old, evergreen enzyme: Carbonic anhydrase, its inhibition and activation. Bioorg. Med. Chem. Lett., 93.","DOI":"10.1016\/j.bmcl.2023.129411"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1080\/13543776.2018.1523897","article-title":"Carbonic Anhydrase Inhibitors and Their Potential in a Range of Therapeutic Areas","volume":"28","author":"Supuran","year":"2018","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.tips.2025.07.002","article-title":"Human carbonic anhydrase modulators: The past, present, and future","volume":"46","author":"Giovannuzzi","year":"2025","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1021\/acs.chemrev.4c00278","article-title":"Multiple Binding Modes of Inhibitors to Human Carbonic Anhydrases: An Update on the Design of Isoform-Specific Modulators of Activity","volume":"125","author":"Alterio","year":"2025","journal-title":"Chem. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100004","DOI":"10.1124\/pharmrev.124.001125","article-title":"Multi- and polypharmacology of carbonic anhydrase inhibitors","volume":"77","author":"Supuran","year":"2025","journal-title":"Pharmacol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1080\/14656566.2025.2474574","article-title":"Polypharmacology of carbonic anhydrase inhibitors and activators","volume":"26","author":"Bonardi","year":"2025","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Singh, P., Arifuddin, M., Supuran, C.T., and Nerella, S.G. (2025). Carbonic anhydrase inhibitors: Structural insights and therapeutic potential. Bioorg. Chem., 156.","DOI":"10.1016\/j.bioorg.2025.108224"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e2400626","DOI":"10.1002\/ardp.202400626","article-title":"The carbonic anhydrase enzymes as new targets for the management of neglected tropical diseases","volume":"358","author":"Renzi","year":"2025","journal-title":"Arch. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.enz.2024.05.004","article-title":"Overview on bacterial carbonic anhydrase genetic families","volume":"55","author":"Capasso","year":"2024","journal-title":"Enzymes"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ronca, R., and Supuran, C.T. (2024). Carbonic anhydrase IX: An atypical target for innovative therapies in cancer. Biochim. Biophys. Acta Rev. Cancer, 1879.","DOI":"10.1016\/j.bbcan.2024.189120"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1080\/17425255.2024.2328152","article-title":"Drug interactions of carbonic anhydrase inhibitors and activators","volume":"20","author":"Supuran","year":"2024","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1021\/acs.jmedchem.6b01607","article-title":"Design and Synthesis of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Treatment of Rheumatoid Arthritis","volume":"60","author":"Bua","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1021\/acs.jmedchem.9b01130","article-title":"Bioisosteric Development of Multitarget Nonsteroidal Anti-Inflammatory Drug-Carbonic Anhydrases Inhibitor Hybrids for the Management of Rheumatoid Arthritis","volume":"63","author":"Bua","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7392","DOI":"10.1021\/acs.jmedchem.0c00636","article-title":"Azidothymidine \u201cClicked\u201d into 1,2,3-Triazoles: First Report on Carbonic Anhydrase-Telomerase Dual-Hybrid Inhibitors","volume":"63","author":"Berrino","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gomez, D.E., Armando, R.G., and Alonso, D.F. (2012). AZT as a telomerase inhibitor. Front. Oncol., 2.","DOI":"10.3389\/fonc.2012.00113"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11432","DOI":"10.1021\/acs.jmedchem.1c00756","article-title":"Mechanisms of the Antiproliferative and Antitumor Activity of Novel Telomerase-Carbonic Anhydrase Dual-Hybrid Inhibitors","volume":"64","author":"Plyasova","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Berrino, E., Carradori, S., Angeli, A., Carta, F., Supuran, C.T., Guglielmi, P., Coletti, C., Paciotti, R., Schweikl, H., and Maestrelli, F. (2021). Dual Carbonic Anhydrase IX\/XII Inhibitors and Carbon Monoxide Releasing Molecules Modulate LPS-Mediated Inflammation in Mouse Macrophages. Antioxidants, 10.","DOI":"10.3390\/antiox10010056"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1021\/acs.jmedchem.2c01706","article-title":"Novel Insights on CAI-CORM Hybrids: Evaluation of the CO Releasing Properties and Pain-Relieving Activity of Differently Substituted Coumarins for the Treatment of Rheumatoid Arthritis","volume":"66","author":"Berrino","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2366236","DOI":"10.1080\/14756366.2024.2366236","article-title":"Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition","volume":"39","author":"Nocentini","year":"2024","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/nrg3296","article-title":"DNa secondary structures: Stability and function of G-quadruplex structures","volume":"13","author":"Bochman","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ccr.2004.06.026","article-title":"Predicting Drug Sensitivity and Resistance: Profiling ABC Transporter Genes in Cancer Cells","volume":"6","author":"Annereau","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Braconi, L., Riganti, C., Parenti, A., Cecchi, M., Nocentini, A., Bartolucci, G., Menicatti, M., Contino, M., Colabufo, N.A., and Manetti, D. (2024). Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold. Molecules, 29.","DOI":"10.3390\/molecules29143290"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Tan, A., Kizilkaya, S., Noma, S.A.A., Ates, B., and Kara, Y. (2022). Novel hybrid isoindole-1,3(2H)-dione compounds containing a 1H-tetrazole moiety: Synthesis, biological evaluation, and molecular docking studies. J. Biochem. Mol. Toxicol., 36.","DOI":"10.1002\/jbt.23015"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1021\/acs.jmedchem.2c01911","article-title":"First-in-Class Dual Hybrid Carbonic Anhydrase Inhibitors and Transient Receptor Potential Vanilloid 1 Agonists Revert Oxaliplatin-Induced Neuropathy","volume":"66","author":"Angeli","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ben\u00edtez-Angeles, M., Morales-L\u00e1zaro, S.L., Ju\u00e1rez-Gonz\u00e1lez, E., and Rosenbaum, T. (2020). TRPV1: Structure, Endogenous Agonists, and Mechanisms. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103421"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"115011","DOI":"10.1016\/j.ejmech.2022.115011","article-title":"Design, synthesis, biological evaluation and crystal structure determination of dual modulators of carbonic anhydrases and estrogen receptors","volume":"246","author":"Tinivella","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1182\/bloodadvances.2024015132","article-title":"Estrogen receptor \u03b2 stimulation as a possible novel therapeutic target for cutaneous T-cell lymphoma","volume":"9","author":"Wilhelm","year":"2025","journal-title":"Blood Adv."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5544","DOI":"10.1021\/jm060531j","article-title":"Carbonic anhydrase inhibitors: Hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX","volume":"49","author":"Vitale","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ertl, P., Altmann, E., and Racine, S. (2023). The most common linkers in bioactive molecules and their bioisosteric replacement network. Bioorg. Med. Chem., 81.","DOI":"10.1016\/j.bmc.2023.117194"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/bs.aihch.2020.10.002","article-title":"Chapter Four\u2014Heterocycles in drug discovery: Properties and preparation","volume":"Volume 134","author":"Rotella","year":"2021","journal-title":"Advances in Heterocyclic Chemistry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"116520","DOI":"10.1016\/j.ejmech.2024.116520","article-title":"Application and challenges of nitrogen heterocycles in PROTAC linker","volume":"273","author":"Li","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"112439","DOI":"10.1016\/j.ejmech.2020.112439","article-title":"Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases","volume":"200","author":"Elzahhar","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"115180","DOI":"10.1016\/j.ejmech.2023.115180","article-title":"4-(5-Amino-pyrazol-1-yl)benzenesulfonamide derivatives as novel multi-target anti-inflammatory agents endowed with inhibitory activity against COX-2, 5-LOX and carbonic anhydrase: Design, synthesis, and biological assessments","volume":"250","author":"Ragab","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2201407","DOI":"10.1080\/14756366.2023.2201407","article-title":"Identification of new 4-(6-oxopyridazin-1-yl)benzenesulfonamides as multi-target anti-inflammatory agents targeting carbonic anhydrase, COX-2 and 5-LOX enzymes: Synthesis, biological evaluations and modelling insights","volume":"38","author":"Badawi","year":"2023","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.4155\/fmc-2023-0201","article-title":"Keto-bridged dual triazole-linked benzenesulfonamides as potent carbonic anhydrase and cathepsin B inhibitors","volume":"15","author":"Vats","year":"2023","journal-title":"Future Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"689","DOI":"10.4155\/fmc-2023-0321","article-title":"Novel 1,2,4-triazoles as selective carbonic anhydrase inhibitors showing ancillary anticathepsin B activity","volume":"16","author":"Kumar","year":"2024","journal-title":"Future Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Abbas, H.S., Nossier, E.S., El-Manawaty, M.A., and El-Bayaa, M.N. (2024). New sulfonamide-based glycosides incorporated 1,2,3-triazole as cytotoxic agents through VEGFR-2 and carbonic anhydrase inhibitory activity. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-62864-9"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"112478","DOI":"10.1016\/j.ejmech.2020.112478","article-title":"Discovery of first-in-class multi-target adenosine A2A receptor antagonists-carbonic anhydrase IX and XII inhibitors. 8-Amino-6-aryl-2-phenyl-1,2,4-triazolo [4,3-a]pyrazin-3-one derivatives as new potential antitumor agents","volume":"201","author":"Ceni","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"113300","DOI":"10.1016\/j.ejmech.2021.113300","article-title":"Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR\/CAIX dual inhibitors","volume":"216","author":"Zhang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4170","DOI":"10.1021\/acs.jmedchem.4c00045","article-title":"Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-\u03b2-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction","volume":"67","author":"Giovannuzzi","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"116434","DOI":"10.1016\/j.ejmech.2024.116434","article-title":"Probing benzenesulfonamide-thiazolidinone hybrids as multitarget directed ligands for efficient control of type 2 diabetes mellitus through targeting the enzymes: \u03b1-glucosidase and carbonic anhydrase II","volume":"271","author":"Gamal","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"9613","DOI":"10.1021\/acs.jmedchem.4c00740","article-title":"Development of Penicillin-Based Carbonic Anhydrase Inhibitors Targeting Multidrug-Resistant Neisseria gonorrhoeae","volume":"67","author":"Bonardi","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Montiel, M., Arrighi, G., Begines, P., Gonz\u00e1lez-Bakker, A., Puerta, A., Fernandes, M.X., Merino-Montiel, P., Montiel-Smith, S., Nocentini, A., and Supuran, C.T. (2025). Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031225"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"117752","DOI":"10.1016\/j.ejmech.2025.117752","article-title":"Rationally designed Pyrazolo[1,5-a]pyrimidines as dual inhibitors of CA IX\/XII and CDK6: A novel approach for NSCLC treatment","volume":"293","author":"Elkotamy","year":"2025","journal-title":"Eur. J. Med. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/9\/1387\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:45Z","timestamp":1760035605000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/9\/1387"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,16]]},"references-count":53,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ph18091387"],"URL":"https:\/\/doi.org\/10.3390\/ph18091387","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,16]]}}}