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

IF 3.6 3区医学 Q2 CHEMISTRY, MEDICINAL

Archiv der Pharmazie Pub Date : 2025-07-29 DOI:10.1002/ardp.70062

Gioele Renzi, Andrea Angeli, Silvia Selleri, Costanza Spadini, Nicolo’ Mezzasalma, Marcus T. Hull, Steven L. Kelly, Clemente Capasso, Clotilde S. Cabassi, Fabrizio Carta, Claudiu T. Supuran

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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.

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新型抗感染药物酮康唑衍生物的设计与合成

将抗真菌药酮康唑（KTZ）的远端哌嗪氮与伯芳基磺胺结合，设计合成了一系列新的化合物。本研究的目的是为新一代马拉色菌抗真菌药物提供基础，这些药物能够抑制羊毛甾醇-14α-去甲基化酶(CYP51；EC 1.14.13.70)以及一个新出现的治疗靶点：碳酸酐酶(CAs；EC 4.2.1.1)。最终化合物在体外显示出与预期靶点的有效相互作用，并且KTZ对马拉色菌属酵母菌的最低抑制浓度相当：马拉色菌ATCC 14521；全球马拉色菌ATCC MYA 4612；厚皮马拉色菌DSM 6172。总的来说，所获得的数据说明了所报道的化合物作为有希望的抗真菌候选药物，在真菌感染的管理中具有很高的安全性。

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来源期刊

Archiv der Pharmazie 医学-化学综合

CiteScore

7.90

自引率

5.90%

发文量

176

审稿时长

3.0 months

期刊介绍： Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.