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

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.

Automated summary

This study evaluated the activity of drug hybrids combining azole antifungal drugs with COX inhibitors. Hybrids derived from ibuprofen and flurbiprofen showed stronger inhibition against Candida species compared to fluconazole and comparable to voriconazole. The hybrids with an S-configured azole pharmacophore exhibited higher potency. These hybrids exert their effects via a dual mode of action and are active against mutants lacking the target of azole drugs.