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

Abstract

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.

Novel Aryl Alkamidazole Derivatives as Multifunctional Antifungal Inhibitors: Design, Synthesis, and Biological Evaluation

“…In this study, the protein crystal of the dual-target enzyme (COX-2, PDB: 3RR3; CYP51, PDB: 5TZ1) was reported (Figure ); their active sites were divided into similar binding regions (COX-2: a 1 and b 1 ; CYP51: a 2 and b 2 ). , The main chain groups of NSAIDs (COX-2 inhibitors) and CYP51 inhibitors were found to be composed of similar hydrophobic aryl structures, which could be located in the upper region (COX-2: a 1 ; CYP51: a 2 ) and formed the stable binding conformation . It is worth noting that the carboxyl group of NSAIDs has been the important cause of gastrointestinal irritation, and when the structure was further derived into the ester or amide group, they could effectively maintain the COX-2 inhibitory ability. , Moreover, the study found that the branched chain groups of CYP51 inhibitors containing azolyl and phenyl structures might simultaneously bind in the bottom active region (COX-2: b 1 ; CYP51: b 2 ) of the dual-target enzyme.…”

Cationic, Steroid-Based Imidazolium Amphiphiles Show Tunable Backbone-Dependent Membrane Selectivity in Fungi

“…Tolerance is detected in up to 60% of clinical isolates, making it a widespread concern. Since tolerance is characterized by slow growth, it becomes detectable after at least 48 h of growth in the presence of the drug, whereas resistance is generally evident after 24 h. , To investigate the potency of the cationic amphiphiles in this study in reducing the tolerant subpopulations, we compared the MIC values measured after 24 h to those measured after 48 h for the eight most active compounds (Table ). Generally, relative to MIC 24 , MIC 48 values remained the same or increased just by one double dilution.…”

Deciphering the Biological Activities of Antifungal Agents with Chemical Probes

“…[12,13] Unfortunately, resistance to these antifungals has increased dramatically in the past decades. [14,15] Azole antifungals perturb fungal cell plasma membrane biogenesis by inhibiting the cytochrome P450 demethylase CYP51, a key enzyme in the synthesis of ergosterol, the sterol of the fungal cell membrane. [1] Although the first azole drug was clinically approved almost four decades ago, fundamental questions regarding the mechanisms of cellular uptake and localization of these drugs had remained unanswered.…”