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  3. Design, synthesis, and biological evaluation of novel 4-aminoquinoline derivatives as potent membrane-targeting antifungal agents

Design, synthesis, and biological evaluation of novel 4-aminoquinoline derivatives as potent membrane-targeting antifungal agents

  • Bioorg Med Chem Lett. 2025 Dec 23:133:130514. doi: 10.1016/j.bmcl.2025.130514.
Jing Du 1,  Wei Wang 2,  Yanni Ma 3,  Chaoyong Cui 1,  Yuwan Zhang 2,  Jian Yang 4,  Rui Yang 5
Affiliations

Affiliations

  • 1 College of Materials, Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu 610059, China.
  • 2 College of Ecological Environment, Chengdu University of Technology, Chengdu 610059, China.
  • 3 Henan Academy of Sciences, Zhengzhou 450002, China.
  • 4 State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; Evaluation and Research Center of Daodi Herbs of Jiangxi Province, Ganjiang New District, 330000, China. Electronic address: [email protected].
  • 5 College of Materials, Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu 610059, China. Electronic address: [email protected].
PMID: 41448441 DOI: 10.1016/j.bmcl.2025.130514
Abstract

This study aimed to develop novel Antifungal agents through the design and synthesis of two series of 4-aminoquinoline derivatives (1-21 and their demethylated analogs 1'-16'). These compounds were synthesized via cyclization in POCl3, amine substitution, and BBr3-mediated demethylation, with structures confirmed by NMR and HRMS. Antifungal evaluation showed that while most compounds were weakly active (MICs ≥128 μg/mL), several-particularly those with 6-position hydroxy or methoxy substituents (14, 16, and 14'-16')-displayed notable activity (MICs = 4-32 μg/mL) against Candida albicans, Candida tropicalis, and Cryptococcus neoformans. Compound 14' exhibited potent fungicidal action against C. albicans (MIC = MFC = 4 μg/mL), rapid time-kill kinetics, membrane disruption evidenced by PI/DAPI staining, and strong biofilm inhibition (>90 % at ≥16 μg/mL). SEM imaging revealed extensive ultrastructural damage to Fungal cells. Importantly, 14' showed low cytotoxicity toward human epithelial cells and favorable in silico predicted ADMET profiles. These findings highlight 14' as a promising lead compound with membrane-targeting Antifungal mechanisms and an improved safety profile relative to amphotericin B.

Keywords

4-Aminoquinoline; Antifungal activity; Biofilm; Membrane-targeting; Structure–activity relationship.

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