{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:43:51Z","timestamp":1785426231174,"version":"3.56.0"},"reference-count":86,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of University and Research","award":["FAR2021"],"award-info":[{"award-number":["FAR2021"]}]},{"DOI":"10.13039\/501100005010","name":"Italian Association for Cancer Research","doi-asserted-by":"publisher","award":["IG24449"],"award-info":[{"award-number":["IG24449"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"award":["IG24449"],"award-info":[{"award-number":["IG24449"]}],"id":[{"id":"https:\/\/ror.org\/02g2x7380","id-type":"ROR","asserted-by":"publisher"}]},{"name":"PRIN PNRR","award":["P2022THN5N"],"award-info":[{"award-number":["P2022THN5N"]}]},{"name":"PRIN PNRR","award":["F53D23012310001"],"award-info":[{"award-number":["F53D23012310001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Carbonic Anhydrases (CAs) represent regulators of cell adaptation to hypoxia, pH regulation, and metabolic fitness. Among cancers, multiple myeloma (MM) is a plasma cell malignancy sustained by hypoxia-driven metabolic adaptation, extracellular acidification, and redox imbalance. Tight regulation of tumor extracellular pH, mediated by Carbonic Anhydrases IX and XII, is crucial for myeloma survival, progression, and stemness, making these isoforms attractive therapeutic targets. Methods: We designed and synthesized a library of terpenoid-based hybrids by derivatizing chlorothymol and 4-isopropyl-3-methylphenol with either the natural coumarin umbelliferon or the 2,2\u2032-dipicolylamine (DPA) scaffold. This chemical strategy aimed to selectively inhibit tumor-associated CAs IX\/XII through coumarin- or DPA-mediated recognition, while terpenoid fragments were introduced to enhance lipophilicity, membrane permeability, and potential redox-modulating properties. The compounds were tested by a Stopped-Flow assay for CA inhibition, in cell-based assays for antiproliferative properties and by means of several antioxidant assays. Results: The most active compounds, connecting the coumarin core to a terpenoid tail, inhibited the targeted CAs in the nanomolar range, showing up higher selectivity over off-target isoforms (I and II). In studies performed on MM cell lines, selected derivatives reduced viability (IC50 = 15.8\u201385.4 \u00b5M) and displayed favorable selectivity over normal cells. In silico investigations suggested that the compounds were able to interact selectively with the target enzymes. Conclusions: Collectively, these results support a dual-targeting strategy in which selective inhibition of tumor-associated CAs, combined with redox modulation, interferes with adaptive mechanisms of MM cells, providing a rational framework for the development of multifunctional agents against metabolically resilient hematological malignancies.<\/jats:p>","DOI":"10.3390\/ph19050717","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T10:15:27Z","timestamp":1777630527000},"page":"717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Coumarin\u2013 and Dipicolylamine\u2013Terpenoid Hybrids as Selective Carbonic Anhydrases IX and XII Inhibitors: Mechanistic Insights and Selective Anti-Cancer Potential"],"prefix":"10.3390","volume":"19","author":[{"given":"Venkatesan","family":"Saravanan","sequence":"first","affiliation":[{"name":"School of Pharmacy, SBV Chennai, Sri Balaji Vidyapeeth, Pondicherry 607402, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1470-7192","authenticated-orcid":false,"given":"Andrea","family":"Angeli","sequence":"additional","affiliation":[{"name":"Neurofarba Department, University of Florence, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1987-0850","authenticated-orcid":false,"given":"Francesco","family":"Melfi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Amodio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University \u201cMagna Gr\u00e6cia\u201d of Catanzaro, Campus \u201cS. Venuta\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9565-2584","authenticated-orcid":false,"given":"Ilenia","family":"Valentino","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University \u201cMagna Gr\u00e6cia\u201d of Catanzaro, Campus \u201cS. Venuta\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Gentile","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-7326","authenticated-orcid":false,"given":"Ilaria","family":"D\u2019Agostino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8357-2730","authenticated-orcid":false,"given":"Kathiravan","family":"Muthukumaradoss","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, SRM College of Pharmacy, Chengalpattu District, Tamil Nadu 603203, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6548-7823","authenticated-orcid":false,"given":"Gokhan","family":"Zengin","sequence":"additional","affiliation":[{"name":"Department of Biology, Science Faculty, Selcuk University, 42130 Konya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2470-9351","authenticated-orcid":false,"given":"Davide","family":"Moi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Vita e dell\u2019Ambiente, Cittadella Universitaria di Monserrato, Universit\u00e0 degli Studi di Cagliari, S.P. 8 CA, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahime","family":"Simsek","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Neurofarba Department, University of Florence, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8698-9440","authenticated-orcid":false,"given":"Simone","family":"Carradori","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1016\/S0140-6736(25)01570-3","article-title":"Global cancer burden: Progress, projections, and challenges","volume":"406","author":"Luo","year":"2025","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"590","DOI":"10.2174\/0118715206259585240105051941","article-title":"An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018\u20132021)","volume":"24","author":"Vishakha","year":"2024","journal-title":"Anticancer Agents Med. 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