{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:15:46Z","timestamp":1787498146542,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T00:00:00Z","timestamp":1668643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes in organisms in all life kingdoms, being involved in pH regulation, metabolic processes and many other physiological and pathological conditions. CA inhibitors and activators thus possess applications as pharmacological agents in the management of a range of diseases. Marine natural products have allowed the identification of some highly interesting CA inhibitors, among which are sulfonamides, phenols, polyamines, coumarins and several other miscellaneous inhibitors, which are reviewed here. Psammaplin C and some bromophenols were the most investigated classes of such marine-based inhibitors and have been used as lead molecules for developing interesting types of potent and, in some cases, isoform-selective inhibitors, with applications as antitumor agents by inhibiting human CA XII and P-glycoprotein activities. Some phenols have shown interesting bacterial and fungal \u03b2-CA inhibitory effects. Marine natural products thus constitute a gold mine for identifying novel CA inhibitors, some of which may lead to the development of novel types of pharmacological agents.<\/jats:p>","DOI":"10.3390\/md20110721","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T06:02:29Z","timestamp":1668751349000},"page":"721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Carbonic Anhydrase Inhibitors from Marine Natural Products"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"first","affiliation":[{"name":"NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Universit\u00e0 degli Studi di Firenze, Via Ugo Schiff 6, 50019 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/j.1365-3040.2011.02364.x","article-title":"Carbonic anhydrase and the molecular evolution of C4 photosynthesis","volume":"35","author":"Ludwig","year":"2012","journal-title":"Plant Cell Environ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"325","DOI":"10.3109\/14756366.2014.910202","article-title":"An overview of the alpha-, beta- and gamma-carbonic anhydrases from Bacteria: Can bacterial carbonic anhydrases shed new light on evolution of bacteria?","volume":"30","author":"Capasso","year":"2015","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1152\/physrev.00018.2021","article-title":"Carbonic anhydrases in metazoan model organisms: Molecules, mechanisms, and physiology","volume":"102","author":"Aspatwar","year":"2022","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrd2467","article-title":"Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators","volume":"7","author":"Supuran","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1042\/BCJ20160115","article-title":"Structure and function of carbonic anhydrases","volume":"473","author":"Supuran","year":"2016","journal-title":"Biochem. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1042\/CS20210040","article-title":"Emerging role of carbonic anhydrase inhibitors","volume":"135","author":"Supuran","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1016\/j.bmc.2012.09.047","article-title":"An \u03b1-carbonic anhydrase from the thermophilic bacterium Sulphurihydrogenibium azorense is the fastest enzyme known for the CO2 hydration reaction","volume":"21","author":"Luca","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3390\/metabo8020025","article-title":"Carbonic Anhydrases and Metabolism","volume":"8","author":"Supuran","year":"2018","journal-title":"Metabolites"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.1080\/14756366.2022.2121393","article-title":"Anti-obesity carbonic anhydrase inhibitors: Challenges and opportunities","volume":"37","author":"Supuran","year":"2022","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s00360-022-01459-0","article-title":"The roles of plasma accessible and cytosolic carbonic anhydrases in bicarbonate (HCO3\u2212) excretion in Pacific hagfish (Eptatretus stoutii)","volume":"192","author":"Giacomin","year":"2022","journal-title":"J. Comp. Physiol. B"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1126\/science.1233692","article-title":"Root effect hemoglobin may have evolved to enhance general tissue oxygen delivery","volume":"340","author":"Rummer","year":"2013","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"McDonald, P.C., Chafe, S.C., Supuran, C.T., and Dedhar, S. (2022). Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside. Cancers, 14.","DOI":"10.3390\/cancers14143297"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1080\/17460441.2017.1253677","article-title":"Advances in structure-based drug discovery of carbonic anhydrase inhibitors","volume":"12","author":"Supuran","year":"2017","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1080\/14756366.2021.1882453","article-title":"Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase","volume":"36","author":"Nocentini","year":"2021","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nrd4510","article-title":"The re-emergence of natural products for drug discovery in the genomics era","volume":"14","author":"Harvey","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.3390\/md9071273","article-title":"Bromophenols in marine algae and their bioactivities","volume":"9","author":"Liu","year":"2011","journal-title":"Mar. Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Dong, H., Dong, S., Erik Hansen, P., Stagos, D., Lin, X., and Liu, M. (2020). Progress of Bromophenols in Marine Algae from 2011 to 2020: Structure, Bioactivities, and Applications. Mar. Drugs, 18.","DOI":"10.3390\/md18080411"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1021\/np501015m","article-title":"Natural Product Primary Sulfonamides and Primary Sulfamates","volume":"78","author":"Mujumdar","year":"2015","journal-title":"J. Nat. Prod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1021\/acs.jnatprod.6b00235","article-title":"Antibacterial Compounds from Marine Bacteria, 2010\u20132015","volume":"80","author":"Schinke","year":"2017","journal-title":"J. Nat Prod."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"561","DOI":"10.4155\/fmc-2017-0223","article-title":"Carbonic anhydrase activators","volume":"10","author":"Supuran","year":"2018","journal-title":"Future Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.4155\/fmc-2021-0222","article-title":"Novel carbonic anhydrase inhibitors","volume":"13","author":"Supuran","year":"2021","journal-title":"Future Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"345","DOI":"10.3109\/14756366.2015.1122001","article-title":"How many carbonic anhydrase inhibition mechanisms exist?","volume":"31","author":"Supuran","year":"2016","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.4155\/fmc-2021-0207","article-title":"Bacterial carbonic anhydrases: Underexploited antibacterial therapeutic targets","volume":"13","author":"Flaherty","year":"2021","journal-title":"Future Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1016\/S0040-4020(01)96120-4","article-title":"Novel marine sponge derived amino acids 13. Additional psammaplin derivatives from Psammaplysilla purpurea","volume":"47","author":"Crews","year":"1991","journal-title":"Tetrahedron"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5462","DOI":"10.1021\/acs.jmedchem.6b00443","article-title":"An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition, and Protein X-ray Structures of Psammaplin C","volume":"59","author":"Mujumdar","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4174","DOI":"10.1021\/acs.jmedchem.9b00282","article-title":"Carbonic Anhydrase XII Inhibitors Overcome Temozolomide Resistance in Glioblastoma","volume":"62","author":"Mujumdar","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1080\/13543784.2021.2014813","article-title":"Carbonic anhydrase inhibitors: An update on experimental agents for the treatment and imaging of hypoxic tumors","volume":"30","author":"Supuran","year":"2021","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"603","DOI":"10.2147\/JEP.S265620","article-title":"Experimental Carbonic Anhydrase Inhibitors for the Treatment of Hypoxic Tumors","volume":"12","author":"Supuran","year":"2020","journal-title":"J. Exp. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.7164\/antibiotics.42.1556","article-title":"Altemicidin, a new acaricidal and antitumor substance. I. Taxonomy, fermentation, isolation and physico-chemical and biological properties","volume":"42","author":"Takahashi","year":"1989","journal-title":"J. Antibiot."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1016\/S0006-291X(82)80063-6","article-title":"Phenol, a competitive inhibitor of CO2 hydration catalyzed by carbonic anhydrase","volume":"108","author":"Simonsson","year":"1982","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.1021\/ja00087a086","article-title":"Two-site binding of phenol in the active site of human carbonic anhydrase II: Structural implications for substrate association","volume":"116","author":"Nair","year":"1994","journal-title":"J. Am. Chem. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/j.bmcl.2008.01.077","article-title":"Carbonic anhydrase inhibitors. Interactions of phenols with the 12 catalytically active mammalian isoforms (CA I\u2013XIV)","volume":"18","author":"Innocenti","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7424","DOI":"10.1016\/j.bmc.2008.06.013","article-title":"Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I\u2013XIV with a series of substituted phenols including paracetamol and salicylic acid","volume":"16","author":"Innocenti","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9101","DOI":"10.1016\/j.bmc.2008.09.028","article-title":"In vitro effects of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymesI and II","volume":"16","author":"Bayram","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1016\/j.bmc.2009.01.067","article-title":"Carbonic anhydrase inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of antioxidant phenols","volume":"17","author":"Supuran","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1016\/j.bmc.2010.01.076","article-title":"Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I\u2013XIV with a series of natural product polyphenols and phenolic acids","volume":"18","author":"Innocenti","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bmc.2009.11.021","article-title":"Carbonic anhydrase inhibitors. Identification of selective inhibitors of the human mitochondrial isozymes VA and VB over the cytosolic isozymes I and II from a natural product-based phenolic library","volume":"18","author":"Davis","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1021\/jm1013242","article-title":"Natural product-based phenols as novel probes for mycobacterial and fungal carbonic anhydrases","volume":"54","author":"Davis","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s11030-010-9271-4","article-title":"Carbonic anhydrase inhibition with natural products: Novel chemotypes and inhibition mechanisms","volume":"15","author":"Supuran","year":"2011","journal-title":"Mol. Divers"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7219","DOI":"10.1016\/j.bmc.2015.10.018","article-title":"New natural product carbonic anhydrase inhibitors incorporating phenol moieties","volume":"23","author":"Karioti","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1039\/a900201d","article-title":"The diversity of naturally occurring organobromine compounds","volume":"28","author":"Gribble","year":"1999","journal-title":"Chem. Soc. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1016\/j.bmcl.2011.12.069","article-title":"Synthesis and carbonic anhydrase inhibitory properties of novel cyclohexanonyl bromophenol derivatives","volume":"22","author":"Menzek","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"467","DOI":"10.3109\/14756366.2011.596836","article-title":"Inhibition of human carbonic anhydrase isozymes I, II and VI with a series of bisphenol, methoxy and bromophenol compounds","volume":"27","author":"Balaydin","year":"2012","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.ejmech.2012.05.025","article-title":"Synthesis and carbonic anhydrase inhibitory properties of novel bromophenols and their derivatives including natural products: Vidalol B","volume":"54","author":"Menzek","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3109\/14756366.2015.1054820","article-title":"The effects of some bromophenols on human carbonic anhydrase isoenzymes","volume":"31","author":"Taslimi","year":"2016","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1021\/jm501573b","article-title":"Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII inhibitory effects of dimethoxybromophenol derivatives incorporating cyclopropane moieties","volume":"58","author":"Topal","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5511","DOI":"10.1021\/jm1003667","article-title":"Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule","volume":"53","author":"Carta","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"374079","DOI":"10.1155\/2014\/374079","article-title":"Natural product polyamines that inhibit human carbonic anhydrases","volume":"2014","author":"Davis","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Stefanachi, A., Leonetti, F., Pisani, L., Catto, M., and Carotti, A. (2018). Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds. Molecules, 23.","DOI":"10.3390\/molecules23020250"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1080\/14756366.2020.1788009","article-title":"Coumarin carbonic anhydrase inhibitors from natural sources","volume":"35","author":"Supuran","year":"2020","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1021\/ja809683v","article-title":"Non-zinc mediated inhibition of carbonic anhydrases: Coumarins are a new class of suicide inhibitors","volume":"131","author":"Maresca","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1021\/jm901287j","article-title":"Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins","volume":"53","author":"Maresca","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.bmc.2012.07.021","article-title":"Natural product coumarins that inhibit human carbonic anhydrases","volume":"21","author":"Davis","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Rafiq, K., Khan, A., Ur Rehman, N., Halim, S.A., Khan, M., Ali, L., Hilal Al-Balushi, A., Al-Busaidi, H.K., and Al-Harrasi, A. (2021). New Carbonic Anhydrase-II Inhibitors from Marine Macro Brown Alga Dictyopteris hoytii Supported by In Silico Studies. Molecules, 26.","DOI":"10.3390\/molecules26237074"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"13946","DOI":"10.1021\/acs.jmedchem.2c01192","article-title":"Discovery of a Potent and Highly Selective Dipeptidyl Peptidase IV and Carbonic Anhydrase Inhibitor as \u201cAntidiabesity\u201d Agents Based on Repurposing and Morphing of WB-4101","volume":"65","author":"Artasensi","year":"2022","journal-title":"J. Med. Chem."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/20\/11\/721\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:20:17Z","timestamp":1760145617000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/20\/11\/721"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,17]]},"references-count":56,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["md20110721"],"URL":"https:\/\/doi.org\/10.3390\/md20110721","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,17]]}}}