Design and Synthesis of Ketoconazole Derivatives as Innovative Anti‐Infective Agents

Abstract

A novel series of compounds was designed and synthesized by combining the distal piperazine nitrogen of the antifungal ketoconazole (KTZ) with primary arylsulfonamides. The aim of this study is to present the basis for a new generation of Malassezia antifungal agents able to inhibit the enzyme lanosterol‐14α‐demethylase (CYP51; EC 1.14.13.70) as well as a newly emergent therapeutic target: carbonic anhydrases (CAs; EC 4.2.1.1). The final compounds showed effective interactions with the intended targets in vitro, as well as KTZ comparable minimum inhibitory concentrations on yeast strains of the Malassezia genus: Malassezia furfur ATCC 14521; Malassezia globosa ATCC MYA 4612; and Malassezia pachydermatis DSM 6172. Overall, the data obtained account for the reported compounds as promising antifungal candidates with high safety profiles for the management of fungal infections