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.