Exploring medium and long arm extensions of 1,2,4-triazole derivatives as Candida albicans 14α-demethylase (CYP51) inhibitors.

IF 4.1 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

RSC medicinal chemistry Pub Date : 2025-03-12 DOI:10.1039/d4md00863d

Marwa Alsulaimany, Faizah A Binjubair, Esra Tatar, Diane E Kelly, Steven L Kelly, Andrew G Warrilow, Mikhail V Keniya, Brian C Monk, Josie E Parker, Claire Simons

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Abstract

Fungal infections have been described as a silent crisis affecting more than one billion people each year. At least 150 million of these cases involve severe and life threatening invasive fungal infections, accounting for approximately 1.7 million deaths annually. 1,2,4-Trizoles such as fluconazole and posaconazole are widely used antifungal agents, but azole resistance is an increasing problem requiring further study. 1,2,4-Triazole derivatives with medium and long arm extensions designed to bind within the Candida albicans CYP51 (CaCYP51) access channel were synthesised to study their inhibition of CaCYP51 (IC₅₀, MIC) and binding affinity (K _d). A long arm extension using the amide linker was found to be most effective (e.g.13), giving an antifungal profile vs. wild-type and resistant model fungal strains comparable with posaconazole.

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探索1,2,4-三唑衍生物作为白色念珠菌14α-去甲基化酶（CYP51）抑制剂的中、长臂延伸

真菌感染被描述为一种无声的危机，每年影响超过10亿人。这些病例中至少有1.5亿例涉及严重和危及生命的侵袭性真菌感染，每年造成约170万人死亡。1,2,4-三唑类药物如氟康唑和泊沙康唑是广泛使用的抗真菌药物，但对唑类药物的耐药性问题日益突出，需要进一步研究。合成了设计用于结合白色念珠菌CYP51 （CaCYP51）通路的具有中臂和长臂延伸的1,2,4-三唑衍生物，以研究它们对CaCYP51的抑制作用（IC50， MIC）和结合亲和力（K d）。使用酰胺连接剂的长臂延伸被发现是最有效的（例如13），与野生型和耐药模型真菌菌株相比，具有与泊沙康唑相当的抗真菌特性。

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来源期刊

RSC medicinal chemistry Multiple-

CiteScore

5.80

自引率

2.40%

发文量

129