Fluconazole-COX Inhibitor Hybrids: A Dual-Acting Class of Antifungal Azoles

Rebecca Elias, Pallabita Basu, Micha Fridman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


When used in combination with azole antifungal drugs, cyclooxygenase (COX) inhibitors such as ibuprofen improve antifungal efficacy. We report the conjugation of a chiral antifungal azole pharmacophore to COX inhibitors and the evaluation of activity of 24 hybrids. Hybrids derived from ibuprofen and flurbiprofen were considerably more potent than fluconazole and comparable to voriconazole against a panel of Candida species. The potencies of hybrids composed of an S-configured azole pharmacophore were higher than those with an R-configured pharmacophore. Tolerance, defined as the ability of a subpopulation of cells to grow in the presence of the drug, to the hybrids was lower than to fluconazole and voriconazole. The hybrids were active against a mutant lacking CYP51, the target of azole drugs, indicating that these agents act via a dual mode of action. This study established that azole-COX inhibitor hybrids are a novel class of potent antifungals with clinical potential.

Original languageEnglish
Pages (from-to)2361-2373
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number3
StatePublished - 10 Feb 2022


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