The Substantial Improvement of Amphotericin B Selective Toxicity Upon Modification of Mycosamine with Bulky Substituents

Abstract

Background: It is assumed that the unfavorable selective toxicity of an antifungal drug Amphotericin B (AmB) can be improved upon chemical modification of the antibiotic molecule. Objective: The aim of this study was verification of the hypothesis that introduction of bulky substituents at the amino sugar moiety of the antibiotic may result in diminishment of mammalian in vitro toxicity of thus prepared AmB derivatives. Methods: Twenty-eight derivatives of AmB were obtained upon chemical modification of the amino group of mycosamine residue. This set comprised 10 N-succinimidyl-, 4 N-benzyl-, 5 Nthioureidyl- and 9 N-aminoacyl derivatives. Parameters characterizing biological in vitro activity of novel compounds were determined. Results: All the novel compounds demonstrated lower than AmB antifungal in vitro activity but most of them exhibited negligible cytotoxicity against human erythrocytes and three mammalian cell lines. In consequence, the selective toxicity of majority of novel antifungals, reflected by the selective toxicity index (STI = EH50/IC50) was improved in comparison with that of AmB, especially in the case of 5 compounds. The novel AmB derivatives with the highest STI, induced substantial potassium efflux from Candida albicans cells at concentrations slightly lower than IC50s but did not trigger potassium release from human erythrocytes at concentrations lower than 100 μg/mL. Conclusion: Some of the novel AmB derivatives can be considered promising antifungal drug candidates.

Quest for the Molecular Basis of Improved Selective Toxicity of All-Trans Isomers of Aromatic Heptaene Macrolide Antifungal Antibiotics

“…It was found that AmB at concentrations about an order of magnitude higher than MIC, self-associate to form dimers or higher oligomers, that are equally toxic to mammalian and fungal cells, whereas AmB monomers, dominating at concentrations close to MIC, are selectively fungicidal [ 9 ]. Several attempts have been made to improve selective toxicity of AmB by its chemical modifications, mainly at the amino group of mycosamine or the carboxyl functionality, resulting in disturbance of self-association ability [ 10 , 11 , 12 , 13 , 14 ].…”

Non‐Toxic Glycosylated Gold Nanoparticle‐Amphotericin B Conjugates Reduce Biofilms and Intracellular Burden of Fungi and Parasites

“…Modification on the mycosamine nitrogen leads to less toxic amphotericin B derivatives without adversely affecting the activity. [ 26 ] Thus, it was reasoned that conjugation of amphothericin B to glycogold nanoparticles via the amine group may reduce the toxicity of the drug. The carboxylic acid moieties on the nanoparticles will impart charge to the conjugate and allow for more water molecules to interact with the nanoparticle for better aqueous dispersion.…”

Synthesis and Biological Evaluation of Amphotericin B Formulations Based on Organic Salts and Ionic Liquids against Leishmania infantum

“…Nevertheless, new methods to cure this disease have been proposed, including host-directed and combinational therapies, drug repurposing and nanotechnology. In addition, ionic liquids, other solvents and nanoparticles [ 18 , 19 , 56 ] have also played a role in what concerns the increase in drug solubilization and the improvement of formulations and delivery [ 17 , 57 ]. Thus, the search for organic salts or ionic liquids as a novel method for easy transformation of amphotericin B in high yields without additional protection/deprotection steps seems desirable to investigate.…”