Amphotericin B Derivative Urea Modification Solubility Toxicity
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Solution Overview
Problem
Amphotericin B derivatives face challenges with high toxicity, nephrotoxicity, hepatotoxicity, and decreased drug efficacy due to low water solubility, limiting their effective treatment for fungal infections.
Innovation Solution
Modification of the 16th position and amino-position of the sugar chain in amphotericin B with specific chemical groups to create compounds with improved antifungal activity, reduced toxicity, and enhanced water solubility, such as those represented by formula (I), which includes various substituents and functional groups to form compounds like —N(RF)—CO—X1 and —CO—NH(RX) structures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If amphotericin B is used as a formulation using deoxycholic acid, then water solubility is improved, but toxicity is high
Solution Approach 1:
The patent modifies the chemical structure of amphotericin B by introducing urea structures at the 16th position and amino sugar modifications, which changes the physical and chemical parameters of the molecule. These structural modifications improve water solubility while simultaneously reducing toxicity by altering how the drug interacts with biological membranes.
Solution Approach 2:
The patent creates composite molecular structures by combining amphotericin B with urea groups and amino sugar modifications. This composite approach allows the drug to maintain its antifungal activity while gaining improved solubility properties and reduced toxic effects through the combined characteristics of the modified structure.
2Object-affected harmful factors
If amphotericin B is formulated using liposome, then toxicity is reduced, but drug efficacy decreases
Solution Approach 1:
The patent changes the chemical parameters of amphotericin B through urea structure introduction and amino sugar modification. These parameter changes enable the drug to achieve both reduced toxicity and maintained or improved efficacy by optimizing the balance between membrane binding affinity and selective toxicity toward fungal cells.
3Quantity of substance
If chemical modification is applied to improve water solubility, then solubility is improved, but drug efficacy may decrease
Solution Approach 1:
The patent systematically modifies chemical parameters at specific positions (16th position urea structures and amino sugar modifications) to optimize the solubility-efficacy balance. The modifications are designed to improve water solubility while preserving the essential pharmacophoric groups necessary for antifungal activity.
Solution Approach 2:
The patent applies localized chemical modifications at specific positions of the amphotericin B molecule (16th position and amino sugar part) rather than global structural changes. This local quality approach allows solubility improvement at specific sites while maintaining the overall structural integrity and antifungal activity of the molecule.
Data Source
AI summary
The present invention is the following Amphotericin B derivative:wherein each symbol is defined in description. The compound of the present invention has 16th position (X) is urea structure, cyclic structure, hydroxyalkyl or substituted monoalkylcarbamoyl. The compound of the present invention has antifungal activity.