Bridged Macrocycle Derivatives for Antimicrobial Efficacy

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Solution Overview

Problem

Current treatments for Cryptococcal meningitis and leishmaniasis are limited by drug toxicity and resistance issues, with a high mortality rate among immunocompromised individuals and inadequate chemotherapeutic agents available, particularly in impoverished regions.

Innovation Solution

Development of novel macrocycle derivatives incorporating bridged macrocycles that form stable complexes with metal ions, exhibiting potent anti-microbial activities effective against Cryptococcus neoformans and Leishmania species, including low concentrations required to inhibit or kill these pathogens.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If standard antifungal drugs like Amphotericin B are used to treat Cryptococcal meningitis, then the treatment can reduce mortality from near 100% to 60-70% in non-AIDS patients, but the treatment is limited by drug toxicity and shows reduced efficacy (only 40% success rate) in AIDS patients

Engineering Contradiction:

Improvetreatment efficacyVSAvoiddrug toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the chemical structure of amphotericin B by replacing the native macrolide ring with various macrocyclic structures (cyclam, cyclen, cyclam derivatives) and adjusting the polyene chain characteristics. These parameter changes in molecular structure aim to maintain antifungal activity while reducing cytotoxicity to mammalian cells, thereby improving the therapeutic index.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite analogs that combine elements of amphotericin B (polyene chain, amino sugar) with synthetic macrocyclic structures. These composite molecules integrate the antifungal properties of the polyene component with the stability and reduced toxicity characteristics of the synthetic macrocycle, achieving a balance between efficacy and safety.

Inventive Principle:

Principle #40Composite materials

2Reliability

If pentavalent antimonials are used to treat visceral leishmaniasis, then the treatment can address the disease burden affecting 1.7 million people annually, but the treatment is toxic and causative agents have developed resistance

Engineering Contradiction:

Improvetreatment effectivenessVSAvoiddrug resistance and toxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying molecular structure - specifically creating macrocyclic derivatives with altered electronic and steric properties compared to traditional pentavalent antimonials. These structural modifications aim to overcome resistance mechanisms while maintaining leishmanicidal activity through different modes of action.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates structural analogs that copy the essential pharmacophoric elements of effective leishmaniasis treatments but with modified macrocyclic cores. These copied and adapted structures seek to preserve therapeutic activity while eliminating the toxicity and resistance issues associated with conventional agents.

Inventive Principle:

Principle #26Copying

3Adaptability or versatility

If a larger number of diverse chemotherapeutic agents are developed to address multiple opportunistic infections in immunocompromised patients, then the range of treatable conditions expands, but the complexity of drug development and clinical management increases

Engineering Contradiction:

Improverange of treatable infectionsVSAvoiddrug development complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent demonstrates universality by showing that macrocyclic derivatives can effectively treat multiple different pathogens including fungi (Cryptococcus neoformans), parasites (Leishmania species), and bacteria. This multi-functionality reduces the need for entirely separate drug development programs for each pathogen type, as a single chemical platform can be optimized for broad-spectrum activity.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The macrocycle derivatives demonstrate significant anti-fungal and anti-parasitic activity, often surpassing the efficacy of standard drugs like Amphotericin B and Pentamidine, offering promising new treatments for opportunistic infections with reduced toxicity.

Implementation Method 1

novel macrocycle derivatives incorporating bridged macrocycles are disclosed... that form stable complexes with metal ions

Methodology Applied

Scientific EffectComplex formation with metal ions:

Data Source

PatentUS12139481B2Compositions comprising macrocycle derivatives incorporating bridged macrocycles and methods of producing and using same

Publication Date: 2024.11.12 SOUTHWESTERN OKLAHOMA STATE UNIVERSITY

AI summary

Compositions are disclosed herein that include macrocycle derivatives incorporating bridged macrocycles. Also disclosed are methods of producing and using the compositions.