Pleuromutilin Derivatives with Meta-Para Phenyl Substituents

Solution Overview

Problem

Current pleuromutilin derivatives lack sufficient antimicrobial activity against clinical relevant bacterial pathogens, particularly Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae, Moraxella catarrhalis, and Escherichia coli, especially when phenyl-ring substituents are not optimally positioned.

Innovation Solution

Development of pleuromutilin compounds with specific phenyl-ring substituents such as 14-O-[(3-Fluoro-phenylsulfanyl)-acetyl]-mutilin, 14-O-[(4-Fluoro-phenylsulfanyl)-acetyl]-mutilin, and others, where X1, X2, and X3 are independently hydrogen, halogen, or alkoxy, enhancing antimicrobial activity by carrying substituents in meta and/or para positions relative to the oxygen/sulfur bond.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If pleuromutilin derivatives are developed with standard phenyl-ring substituents, then basic antimicrobial activity is achieved, but activity against clinical relevant bacterial pathogens is insufficient

Engineering Contradiction:

Improveantimicrobial activityVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies local quality by specifically positioning substituents at meta and/or para positions on the phenyl ring rather than random substitution. This localized structural modification at specific positions enhances antimicrobial activity against clinical pathogens while maintaining reasonable molecular complexity. The focused substitution pattern optimizes interaction with bacterial targets without unnecessary structural elaboration.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying substituent types (halogen, alkoxy, hydroxy) and their positions (meta, para) on the phenyl ring. This parametric optimization of molecular structure leads to enhanced antimicrobial activity. Specific combinations of substituents at specific positions create optimal binding affinity and biological activity while avoiding excessive molecular complexity.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If phenyl-ring substituents are added to enhance antimicrobial activity, then activity against clinical pathogens improves, but molecular structure becomes more complex

Engineering Contradiction:

Improveantimicrobial activity against clinical pathogensVSAvoidmolecular structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies local quality by specifically positioning substituents at meta and/or para positions on the phenyl ring rather than random substitution. This localized structural modification at specific positions enhances antimicrobial activity against clinical pathogens while maintaining reasonable molecular complexity. The focused substitution pattern optimizes interaction with bacterial targets without unnecessary structural elaboration.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying substituent types (halogen, alkoxy, hydroxy) and their positions (meta, para) on the phenyl ring. This parametric optimization of molecular structure leads to enhanced antimicrobial activity. Specific combinations of substituents at specific positions create optimal binding affinity and biological activity while avoiding excessive molecular complexity.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If multiple substituent types are used on the phenyl ring, then antimicrobial activity is enhanced, but synthesis complexity increases

Engineering Contradiction:

Improveantimicrobial activityVSAvoidsynthesis complexity

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent employs parameter changes by systematically varying substituent types (halogen, alkoxy, hydroxy) and their positions (meta, para) on the phenyl ring. This parametric optimization of molecular structure leads to enhanced antimicrobial activity. Specific combinations of substituents at specific positions create optimal binding affinity and biological activity while avoiding excessive molecular complexity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by specifically positioning substituents at meta and/or para positions on the phenyl ring rather than random substitution. This localized structural modification at specific positions enhances antimicrobial activity against clinical pathogens while maintaining reasonable molecular complexity. The focused substitution pattern optimizes interaction with bacterial targets without unnecessary structural elaboration.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS9061980B2Organic compounds

Publication Date: 2015.06.23 HONG KONG KING FRIEND IND CO LTD

AI summary

A compound of formula (I) wherein Y is oxygen or sulfur, and X1, X2 and X3 are independently of each other hydrogen, halogen, hydroxy or linear or branched (C1-6)-alkoxy, or hydroxy-(C1-6)alkyl or (C1-6)alkoxy-(C1-6)alkyl, mono- or dihalogenated (C1-6)-alkyl, amino(C1-6)-alkyl, hydroxy(C1-6)-alkyl, with one of the two provisos that: (1) at least of X1, X2 and X3 is other than hydrogen, and (2) X2 is other than hydroxy, when X1 and X3 are hydrogen.