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

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. Azole conjugates often outperform parent azoles in better antifungal properties. To develop cheap and highly available azole conjugates, we used ketoconazole (KTZ) as a molecular handle to introduce suitable linkers, which would maintain KTZ indigenous activity. Some linker‐modified KTZs showed superior activity compared to KTZ.