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，尽管由于其自聚集导致的严重毒性限制了其临床应用。本研究中，我们通过对C16-COOH和C3′-NH2位置的二酰胺化策略进行应用，通过抑制自聚集来提升其治疗特性。研究发现，位于C16酰胺残基的碱性氨基酸对于活性有益，而亲脂片段则有助于降低毒性。此外，C3′酰胺位置的N-甲基氨基乙酰和氨基乙酰基团有助于维持抗真菌的抑菌效果。这一改性工作最终导致了化合物36（ED50 = 0.21 mg/kg）的发现，其在小鼠模型中表现出比迄今为止最优的衍生物氨酰胺更强的1.5倍抗真菌活性，低自聚集倾向，因而具有低急性毒性。随着治疗指数的提升和良好的药代动力学特性，化合物36具有作为第二代多烯类抗真菌药物的进一步开发潜力。