12-epi-mutilins with inverted C-12 stereochemistry
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Solution Overview
Problem
Current pleuromutilin derivatives lack effective activity against Gram-negative bacteria, particularly Escherichia coli, due to limitations in stereochemistry and substituent composition at the C-12 position of the mutilin ring.
Innovation Solution
Development of 12-epi-mutilins with inverted stereochemistry at the C-12 methyl group and a second substituent containing a nitrogen atom, such as acetyl or amino groups, enhancing antimicrobial activity against both Gram-negative and Gram-positive bacteria.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional pleuromutilin derivatives with natural stereochemistry are used, then activity against Gram-positive bacteria is maintained, but activity against Gram-negative bacteria is insufficient
Solution Approach 1:
The patent applies parameter changes by inverting the stereochemistry at the C-12 position of the mutilin ring and introducing nitrogen-containing substituents. This structural modification transforms the molecular parameters to achieve improved activity against Gram-negative bacteria while retaining activity against Gram-positive bacteria, thereby resolving the contradiction between targeted efficacy and broad-spectrum coverage
Solution Approach 2:
The invention implements local quality by specifically modifying the C-12 position of the mutilin ring with nitrogen-containing groups while keeping the rest of the molecular structure intact. This localized modification at a specific position enables selective improvement of Gram-negative bacterial activity without compromising the inherent activity against Gram-positive bacteria
2Reliability
If the methyl group stereochemistry at C-12 is inverted to improve Gram-negative activity, then activity against Escherichia coli increases, but structural complexity increases
Solution Approach 1:
The patent changes the stereochemical parameter at C-12 from the natural configuration to the inverted configuration, and introduces nitrogen-containing substituents. This parameter modification achieves enhanced activity against Escherichia coli while maintaining a relatively simple molecular framework, thus resolving the contradiction between targeted efficacy and structural simplicity
3Reliability
If nitrogen-containing substituents are introduced at C-12 to enhance antimicrobial activity, then MIC values decrease, but synthesis complexity increases
Solution Approach 1:
The invention introduces nitrogen-containing substituents specifically at the C-12 position of the mutilin ring, creating a localized functional modification. This approach achieves decreased MIC values (improved antimicrobial activity) while concentrating the synthetic effort at a specific position, thereby managing synthesis complexity more effectively than comprehensive molecular redesign
Data Source
AI summary
A compound selected from 14-O-[((Alkyl-, cycloalkyl-, heterocycloalkyl-, heteoroaryl-, or aryl)-sulfanyl)-acetyl]-12-epi-mutilins, or 14-O-[((Alkyl-, cycloalkyl-, heterocycloalkyl-, heteoroaryl-, or aryl)-oxy)-acetyl]-12-epi-mutilins, wherein 12-epi-mutilin is characterized in that the mutilin ring at position 12 is substituted by two substituents, the first substituent at position 12 of the mutilin ring is a methyl group which methyl group has the inverse stereochemistry compared with the stereochemistry of the methyl group at position 12 of the naturally occurring pleuromutilin ring, the second substituent at position 12 of the mutilin ring is a hydrocarbon group comprising at least one nitrogen atom and all other substituents of the mutilin ring having the same stereochemistry compared with the stereochemistry of the substituents at the corresponding positions in the naturally occurring pleuromutilin ring; optionally in the form of a salt and/or solvate, wherein the naturally occurring pleuromutilin is of formulaprocesses for the preparation of such compounds and their use as pharmaceuticals.