Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold

Bader I. Huwaimel, Sravan K. Jonnalagadda, Shirisha Jonnalagadda, Shikha Kumari, Alessio Nocentini, Claudiu T. Supuran, Paul C. Trippier

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor-associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.

Original languageEnglish (US)
Pages (from-to)681-702
Number of pages22
JournalDrug Development Research
Issue number4
StatePublished - Jun 2023


  • carbonic anhydrase IX inhibitors
  • carbonic anhydrases XII inhibitor
  • coumarin
  • structure–activity relationship

ASJC Scopus subject areas

  • Drug Discovery


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