Piperazine‐Modified Ketoconazole Derivatives Show Increased Activity against Fungal and Trypanosomatid Pathogens

Abstract

Ketoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ′ efficacy and safety no longer justify its use as a first‐line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we selected KTZ as a molecular scaffold to introduce such chemical modifications. We prepared a series of piperazine‐modified KTZ derivatives and we evaluated their in vitro antifungal and antitrypanosomal activity against fourteen strains of pathogenic fungi and two strains of Trypanosoma parasites. Several compounds were more effective against the pathogens than KTZ. Compound 5 was 24 times more potent against Aspergillus flavus and 8 times more potent against A. fumigatus than KTZ, with similarly low cytotoxicity to HEK cells up to 100 μM. Derivative 6 had 9‐ and 7‐fold higher activity against T. brucei gambiense and T. brucei brucei than KTZ, respectively, and inhibited trypanosoma growth at single micromolar EC50 values. Combined, our findings will foster further research of piperazine‐modified KTZs as promising antifungal and antiparasitic drugs towards enhancing the properties of both KTZ and other azole derivatives.

Searching for Conjugates as New Structures for Antifungal Therapies

“…Their activity is partly attributed to inhibition of CYP51 (sterol 14αdemethylase) activity, which is because the azole part responsible for enzyme binding is not modified. 17 A similar effect is also attributed to quinolidine-2,4-thiazolidinone derivatives (Figure 2c), for which the molecular docking study suggested their affinity for 14α-demethylase. 18 Meanwhile, studies on the effect of chemical modification on the antifungal activity of indole-triazole conjugates (Figure 2d) showed that structures containing a phenyl substituent (R1) achieved MIC values analogous to those of fluconazole (MIC 250 μg/mL) against C. albicans.…”

“…Thus, antifungal activity is accompanied by mitochondrial dysfunction and elevated levels of reactive oxygen species . The piperazine ring has also been used to modify the structure of ketoconazole (KTZ) . Of the 16 compounds, four (Figure b) showed antifungal activity equal to or superior to that of the parent compound (KTZ).…”

“…Of the 16 compounds, four (Figure b) showed antifungal activity equal to or superior to that of the parent compound (KTZ). Their activity is partly attributed to inhibition of CYP51 (sterol 14α-demethylase) activity, which is because the azole part responsible for enzyme binding is not modified . A similar effect is also attributed to quinolidine-2,4-thiazolidinone derivatives (Figure c), for which the molecular docking study suggested their affinity for 14α-demethylase …”

“…16 The piperazine ring has also been used to modify the structure of ketoconazole (KTZ). 17 Of the 16 compounds, four (Figure 2b) showed antifungal activity equal to or superior to that of the parent compound (KTZ). Their activity is partly attributed to inhibition of CYP51 (sterol 14αdemethylase) activity, which is because the azole part responsible for enzyme binding is not modified.…”

Ketoconazole-loading strategy to improve antifungal activity and overcome cytotoxicity on human renal proximal tubular epithelial cells

“…The treatment of choice for the diseases is based on the use of antifungal drugs such as voriconazole, itraconazole, posaconazole, ketoconazole, thiabendazole and more recently, isavuconazole. As a matter of fact, in the literature, it is often confused as a genus/species studied in studies with ketoconazole, other antifungals or plant secondary metabolites [2,4,5,8].…”