Quinoline Derivatives Inhibit ATP Synthase to Combat Resistant Bacteria
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Solution Overview
Problem
The emergence of antibiotic-resistant bacterial strains, such as penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, and methicillin-resistant Staphylococcus aureus, poses a significant challenge in treating bacterial infections, leading to prolonged illnesses, increased morbidity, mortality, and financial burdens on healthcare systems due to the limited effectiveness of existing antibiotics.
Innovation Solution
The use of quinoline derivatives, specifically compounds described in WO 2004/011436, which exhibit activity against Staphylococci, Enterococci, and Streptococci, including resistant strains, as a medicament to treat bacterial infections by administering an effective amount of these compounds to mammals, particularly humans.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If first-line antibiotic agents are used, then treatment of bacterial infections is effective, but resistance to these antibiotics emerges
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of known quinoline derivatives (compounds of formula I with specific R1, R2, R3, R4, R5, R6 substituents) to create new compounds with altered biological properties. These structural parameter changes result in compounds that maintain antibacterial activity while overcoming resistance mechanisms that have developed against first-line antibiotics, thereby treating infections caused by resistant strains of Staphylococci, Enterococci, and Streptococci
2Reliability
If new antibiotic compounds are developed to treat resistant strains, then treatment effectiveness improves, but development time and cost increase
Solution Approach 1:
The patent applies preliminary action by building upon previously discovered quinoline derivatives (WO 2004/011436) that showed activity against Mycobacteria. By conducting preliminary structural modifications and screenings on this known scaffold, the inventors efficiently identified compounds with activity against non-tuberculous bacteria including resistant Staphylococci, Enterococci, and Streptococci, thereby reducing the overall development time compared to de novo drug discovery
Solution Approach 2:
The patent applies copying by using the quinoline derivative scaffold from antimycobacterial compounds as a template. The core molecular structure is copied and adapted with specific substituent patterns (R1-R6 groups) to create new compounds that replicate the successful pharmacological properties of the original compounds while gaining new spectrum of activity against resistant bacterial strains
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 quinoline derivatives demonstrate bactericidal or bacteriostatic activity against gram-positive and gram-negative bacteria, including resistant strains, effectively treating infections by inhibiting F1F0 ATP synthase, thereby reducing cellular ATP levels and killing bacteria.
Implementation Method 1
The quinoline derivatives demonstrate bactericidal or bacteriostatic activity against gram-positive and gram-negative bacteria, including resistant strains, effectively treating infections by inhibiting F1F0 ATP synthase, thereby reducing cellular ATP levels and killing bacteria.
Data Source
AI summary
The present invention relates to the use of a compound for the manufacture of a medicament for the treatment of a bacterial infection, said compound being a compound of formula (I) a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or a N-oxide form thereof, wherein R1 is hydrogen, halo, polyhaloC1-6alkyl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxy, Ar or Het; p is an integer equal to 1 or 2; R2 is C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy or C1-6alkylt hio ; R3 is C1-6alkyl, Ar, Het or Het1; R4 and R5 each independently are hydrogen, C1-6alkyl or benzyl; or R4 and R5 together and including the N to which they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said rings may optionally be substituted with C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, hydroxyC1-6alkyl, C1-6alkyloxy, amino, mono- or di(C1-6alkyl)amino, C1-6alkylt hio, C1-6alkyloxyC1-6alkyl, C1-6alkylt hioC1-6alkyl or pyrimidinyl; R6 is hydrogen, halo, polyhaloC1-6alkyl, C1-6alkyl, C1-6alkylo xy, C1-6alkylt hio ; or two vicinal R6 radicals may be taken together to form a bivalent radical of formula -CH=CH-CH=CH- ; r is an integer equal to 1 or 2; R7 is hydrogen, C1-6alkyl, Ar, Het or Het1; provided that the bacterial infection is other than a Mycobacterial infection.