Luo Zirui, Liu Rongrong, Sun Yixiang, Zhao Leimeng, Zhang Jiachen, Li Kejian, Gao Zixuan, Liu Nian, Zhang Haoyu, Wu Xudong, Liu Jingming, Hao Wenzhan, Su Xin, Zhao Dongmei, Cheng Maosheng
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
Eur J Med Chem. 2025 Oct 15;296:117817. doi: 10.1016/j.ejmech.2025.117817. Epub 2025 May 28.
Invasive fungal infections (IFIs) are a serious infectious disease worldwide, characterized by high mortality and morbidity. Azole drugs are the most commonly used drugs for the treatment of invasive fungal infections. However, because azole drugs can easily interact with human CYPs metabolic enzymes, the risk of drug-to-drug interaction is high when multiple drugs are used together with azole drugs in clinic. As the problem of fungal drug resistance is becoming increasingly serious, there is an urgent need to develop new CYP51 inhibitors. The successful marketing of Oteseconazole has brought the development of azole drugs into a new era. Compound A33, previously discovered by our group, showed excellent antifungal activity against a variety of pathogenic and drug-resistant fungi. Nevertheless, owing to its structural characteristics, it showed poor selectivity for the human CYPs family and extremely poor metabolic stability. To address the above problem, inspired by the reduced CYP inhibition observed in Oteseconazole, we replaced its triazole group with tetrazole and attempted deuteration strategies and carbonyl introduction to block the metabolic site. This modification led to the synthesis of compounds V01-V24, in which V23 showed broad-spectrum activity and resistance characteristics, especially against Aspergillus fumigatum (MIC = 1 μg/mL), which had no inhibitory activity for many azole drugs. Compared to A33, the introduction of the tetrazole structure reduced its inhibitory activity against the human CYPs family. Furthermore, V23 could prevent fungal phase transformation and biofilm formation, resulting in satisfactory fungicidal activity. V23 showed negligible toxicity toward SH-SY5Y and HUVEC cells, and in vivo pharmacodynamic studies have shown that V23 has significant in vivo antifungal activity. In conclusion, the discovery of compound V23 is a successful exploration of a new tetrazole CYP51 inhibitor for the treatment of invasive fungal infections.
侵袭性真菌感染（IFI）是一种全球范围内严重的传染病，具有高死亡率和高发病率。唑类药物是治疗侵袭性真菌感染最常用的药物。然而，由于唑类药物容易与人细胞色素P450（CYPs）代谢酶相互作用，临床上唑类药物与多种药物联合使用时药物相互作用的风险很高。随着真菌耐药问题日益严重，迫切需要开发新型CYP51抑制剂。奥替康唑的成功上市使唑类药物的发展进入了一个新时代。我们小组先前发现的化合物A33对多种致病性和耐药真菌表现出优异的抗真菌活性。然而，由于其结构特点，它对人CYPs家族的选择性较差，代谢稳定性极差。为了解决上述问题，受奥替康唑中观察到的CYP抑制作用降低的启发，我们用四氮唑取代其唑基团，并尝试采用氘代策略和引入羰基来阻断代谢位点。这种修饰导致了化合物V01-V24的合成，其中V23表现出广谱活性和耐药特性，尤其是对烟曲霉（MIC = 1μg/mL），而许多唑类药物对其没有抑制活性。与A33相比，四氮唑结构的引入降低了其对人CYPs家族的抑制活性。此外，V23可以阻止真菌的形态转变和生物膜形成，从而产生令人满意的杀菌活性。V23对SH-SY5Y和人脐静脉内皮细胞（HUVEC）的毒性可忽略不计，体内药效学研究表明V23具有显著的体内抗真菌活性。总之，化合物V23的发现是对一种新型四氮唑CYP51抑制剂治疗侵袭性真菌感染的成功探索。
