Design, Synthesis, and Structure–Activity Relationship Studies of Bisamide Derivatives of Amphotericin B with Potent Efficacy and Low Toxicity

Amphotericin B (AMB, 1) is the most powerful antibiotic
in treating potentially life-threatening invasive fungal infections
(IFIs), though severe toxicity derived from self-aggregation greatly
limits its clinical application. Herein, we applied a bisamidation
strategy at the C16-COOH and C3′-NH2 to improve
the therapeutic properties by suppressing self-aggregation. It was
found that basic amino groups at the residue of C16 amide were beneficial
to activity, while lipophilic fragments contributed to toxicity reduction.
Additionally, N-methyl-amino acetyl and amino acetyl
moieties at C3′ amide could help keep the fungistatic effectiveness.
The modification work culminated in the discovery of 36 (ED50 = 0.21 mg/kg), which exerted a 1.5-fold stronger
antifungal efficacy than amphamide, the optimal derivative theretofore,
in mice, low self-aggregation propensity, and thus low acute toxicity.
With the improvement in therapeutic index and good PK profile, 36 is promising for further development as a second-generation
polyene antifungal agent.

两性霉素B（AMB，1）是治疗可能危及生命的侵袭性真菌感染（IFIs）的最强效抗生素，尽管由于自身聚集导致的严重毒性大大限制了其临床应用。本研究中，我们通过在C16-COOH和C3′-NH2位点上采用双酰胺化策略，通过抑制自身聚集来改善其治疗特性。研究发现，位于C16酰胺残基处的碱性氨基酸对活性有益，而亲脂性片段有助于降低毒性。此外，C3′酰胺上的N-甲基氨基乙酰和氨基乙酰基团有助于维持真菌抑菌效果。经过改良工作，最终发现了化合物36（ED50 = 0.21 mg/kg），它在小鼠中的抗真菌效力比迄今为止最优的衍生物两性霉素酰胺提高了1.5倍，具有低自我聚集倾向和因此低的急性毒性。随着治疗指数的提高和良好的药代动力学/药效学（PK）特征，化合物36有望进一步开发为第二代多烯类抗真菌药物。