2. Academic Validation
  3. Structure-Based Optimization of Novel Sterol 24-C-Methyltransferase Inhibitors for the Treatment of Candida albicans Infections

Structure-Based Optimization of Novel Sterol 24-C-Methyltransferase Inhibitors for the Treatment of Candida albicans Infections

  • J Med Chem. 2024 Jun 13;67(11):9318-9341. doi: 10.1021/acs.jmedchem.4c00470.
Xue Wang 1,  Xueyang Jin 1,  Fabao Zhao 2,  Zejun Xu 1,  Wenzhuo Tan 1,  Jiaozhen Zhang 1,  Yuliang Xu 3,  Xiaoyi Luan 1,  Min Fang 1,  Zhiyu Xie 4,  Wenqiang Chang 1,  Hongxiang Lou 1
Affiliations

Affiliations

  • 1 Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 3 Department of Clinical Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250013, China.
  • 4 Key Laboratory of Micro-Nano Materials for Energy Storage and Conversion of Henan Province, Institute of Surface Micro and Nano Materials, College of Chemical and Materials Engineering, Xuchang University, Xuchang 461002, China.
PMID: 38764175 DOI: 10.1021/acs.jmedchem.4c00470
Abstract

Interfering with sterol biosynthesis is an important strategy for developing safe and effective Antifungal drugs. We previously identified compound H55 as an allosteric inhibitor of the fungal-specific C-24 sterol methyltransferase Erg6 for treating Candida albicans infections. Herein, 62 derivatives of H55 were designed and synthesized based on target-ligand interactions to identify more active candidates. Among them, d28 displayed the most potent antivirulence ability (MHIC50 = 0.25 μg/mL) by targeting Erg6, exhibiting an 8-fold increase in potency compared with H55. Moreover, d28 significantly outperformed H55 in inhibiting cell adhesion and biofilm formation, and exhibited minimal cytotoxicity and negligible potential to induce drug resistance. Of note, the coadministration of d28 and other sterol biosynthesis inhibitors, such as tridemorph or terbinafine, demonstrated a strong synergistic Antifungal action in vitro and in vivo in a murine skin Infection model. These results support the potential application of d28 in the treatment of C. albicans infections.

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