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

Abstract

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.

• Authors: Huijun Ma, Anran Qian, Yazhou Zheng, Xin Meng, Ting Wang, Yinyong Zhang, Lulu Sun, Feng Zou, Bomei Zhao, Shuhua Zhang, Dan Zhang, Yushe Yang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 13 Pg. 8897-8913 (07 14 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35786969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Antifungal Agents
• Amphotericin B

Topics

• Amides (toxicity)
• Amphotericin B (therapeutic use, toxicity)
• Animals
• Antifungal Agents (toxicity)
• Mice
• Structure-Activity Relationship