酮康唑衍生物作为新型抗感染药物的设计与合成

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

作者信息

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

机构信息

NEUROFARBA Department, Section of Pharmaceutical and Nutraceutical Sciences, Sesto Fiorentino, Università degli Studi di Firenze, Florence, Italy.

Department of Veterinary Science, University of Parma, Parma, Italy.

出版信息

Arch Pharm (Weinheim). 2025 Jul;358(7):e70062. doi: 10.1002/ardp.70062.

DOI:10.1002/ardp.70062

PMID:40726219

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.

摘要

通过将抗真菌药酮康唑（KTZ）哌嗪环远端的氮原子与芳基磺酰胺结合，设计并合成了一系列新型化合物。本研究旨在为新一代马拉色菌抗真菌药物奠定基础，这类药物能够抑制羊毛甾醇-14α-去甲基酶（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）。最终化合物在体外与预期靶点表现出有效的相互作用，并且对马拉色菌属酵母菌株的最低抑菌浓度与KTZ相当，这些酵母菌株包括：糠秕马拉色菌ATCC 14521、球形马拉色菌ATCC MYA 4612和厚皮马拉色菌DSM 6172。总体而言，所获得的数据表明这些报道的化合物是有前景的抗真菌候选药物，在治疗真菌感染方面具有高安全性。