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.