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′-NH 2 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 (ED 50 = 0.21 mg/kg), which exerted a 1.5-fold stronger antifungal efficacy than amphamide, the optimal derivative theretofore, in mice, low selfaggregation 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.

3-Methoxyazetidin-2-one Functionalized CuO–CB Microfibrils: A Drug Formulation with Controlled Release and Enhanced Synergistic Antibacterial Activities

“…Around 60% of the suffering in patients is caused due to different types of infections acquired during treatment in hospitals. , To treat these infections, several classes of antimicrobial agents have frequently been administrated by medical practitioners. , However, the excessive usage of these antimicrobial agents has created resistance in microorganisms. , Consequently, the conventional antibiotics including different types of β-lactams work with reduced potency and considerably enhanced morality rate among patients . Due to the inferior potency of commercially available antibiotics, microbial infection in patients and animals has become extremely challenging to treat. − As a result, the hospitalized time of diseased persons has been stretched longer, with higher treatment charges as well as additional suffering for patients . Moreover, the increment in the death rate is unavoidable in immune-deficient patients with elemental health issues. , Up to now, different endeavors including modification in antibiotic structures as well as integration of antimicrobes with high productivity rate have been administrated to combat bacterial resistance .…”