Quinoline Derivatives Targeting F1F0 ATP Synthase for Tuberculosis
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Solution Overview
Problem
Current treatments for tuberculosis, particularly multi-drug resistant strains and latent infections, are lengthy, require multiple drugs, and face challenges with patient compliance and emerging antibiotic resistance, necessitating new compounds with improved efficacy and mechanism of action.
Innovation Solution
Development of novel substituted quinoline derivatives with an unsaturated carbon chain attached to the 3-position of the quinoline nucleus, offering enhanced activity against Mycobacterium tuberculosis, including latent and drug-resistant strains, and other bacterial pathogens like Streptococci and Staphylococci, by inhibiting bacterial growth and potentially targeting the F1F0 ATP synthase.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current standard tuberculosis treatment regimens are used, then bacterial burden is reduced and patients become noninfectious, but treatment duration is lengthy (6 months or more) and requires multiple drugs
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of quinoline derivatives - specifically introducing an unsaturated carbon chain at the 3-position of the quinoline nucleus with specific substitutions at positions 4 and 7. This structural parameter change results in compounds with enhanced sterilizing activity that can shorten treatment duration while maintaining effectiveness against M. tuberculosis including drug-resistant strains
Solution Approach 2:
The patent employs composite materials by combining the quinoline core structure with specific substituent groups (unsaturated carbon chain, heterocyclic rings, aromatic groups) to create a composite molecular structure. This composite approach allows the drug to achieve both potent bactericidal activity and sterilizing effect, potentially enabling shorter treatment regimens
2Reliability
If current tuberculosis treatment regimens are used, then bacterial burden is reduced, but patient compliance is challenging due to lengthy treatment and frequent supervision requirements
Solution Approach 1:
By changing the chemical parameters of the quinoline derivative structure - specifically the unsaturated carbon chain length and substitution patterns - the patent aims to produce compounds with improved pharmacokinetic properties including longer half-life and sustained activity, which would reduce dosing frequency and improve patient compliance
3Reliability
If existing antibiotic treatments are used, then some bacterial infections are treated, but multi-drug resistant strains emerge and existing therapies become ineffective
Solution Approach 1:
The patent applies inversion by developing a completely new mechanism of action - targeting F1F0 ATP synthase - rather than continuing to modify existing antibiotic classes. This novel approach, achieved through the specific quinoline derivative structure with unsaturated carbon chain, bypasses existing resistance mechanisms and demonstrates activity against MDR-TB strains
Solution Approach 2:
The composite molecular structure combining quinoline core with specific heterocyclic and aromatic substitutions creates a unique drug molecule with a novel mechanism of action (F1F0 ATP synthase inhibition), providing versatility against both susceptible and drug-resistant bacterial strains
4Reliability
If current tuberculosis treatment regimens are used, then intensive bactericidal phase reduces bacterial burden, but continuation sterilizing phase requires 4-6 months to eliminate persisting bacilli
Solution Approach 1:
The patent applies parameter changes by optimizing the quinoline derivative structure - specifically the unsaturated carbon chain at position 3 and substitutions at positions 4 and 7 - to enhance sterilizing activity. This structural modification aims to eliminate persisting bacilli more rapidly, potentially shortening the 4-6 month sterilizing phase while maintaining reliable sterilizing effect
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
These compounds demonstrate broad-spectrum activity against both gram-positive and gram-negative bacteria, including resistant strains, providing a shorter treatment duration, improved compliance, and effectiveness against latent and drug-resistant TB, potentially addressing the limitations of existing therapies.
Implementation Method 1
by inhibiting bacterial growth and potentially targeting the F1F0 ATP synthase
Data Source
AI summary
The present invention relates to novel subst ituted quinoline derivatives according to the general Formula (Ia) or Formula (Ib): including any stereochemically isomeric form thereof, wherein 10 Q represents a radical of formula a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. The claimed compounds are useful for the treatment of a bacterial infection. Also claimed is a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of the claimed compounds, the use of the claimed compounds or composit ions for the manufacture of a medicament for the treatment of a bacterial infection and a process for preparing the claimed compounds.