PBD Antibacterial Agents Membrane Permeability
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Solution Overview
Problem
Current pyrrolobenzodiazepine (PBD) compounds are ineffective against Gram-negative bacterial species due to inability to traverse their outer membrane and exhibit high cytotoxicity, limiting their use as antibacterial agents, especially against multidrug-resistant pathogens like Pseudomonas aeruginosa and Acinetobacter baumannii.
Innovation Solution
Development of novel compounds of formula (I) and their pharmaceutically acceptable salts and solvates, which include specific heterocyclic groups and optional double bonds, designed to enhance permeability through bacterial membranes and inhibit efflux pumps, allowing effective treatment of both Gram-positive and Gram-negative bacterial infections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PBD compounds are used to treat bacterial infections, then antibacterial activity is achieved, but cytotoxicity increases
Solution Approach 1:
The patent introduces a lipophilic group at a specific position (position 11a) of the PBD molecule. This localized modification changes the properties of that specific region of the molecule, making it more lipophilic and enabling membrane traversal, while the rest of the molecule retains its DNA-binding antibacterial activity. This resolves the contradiction by improving membrane permeability without compromising the core antibacterial function.
Solution Approach 2:
The patent creates a composite molecular structure by combining the PBD core structure with an additional lipophilic group. This composite structure integrates the DNA-binding capability of PBD with the membrane-traversing capability of the lipophilic group, achieving both antibacterial activity and reduced cytotoxicity through the synergistic combination of functional groups.
2Reliability
If PBD compounds are designed for Gram-negative bacteria, then membrane permeability is improved, but selectivity against Gram-positive bacteria is lost
Solution Approach 1:
The patent designs a PBD derivative with a lipophilic group that provides dual functionality: it enables traversal of the outer membrane of Gram-negative bacteria while preserving the ability to bind DNA and exert antibacterial effects. The modification makes the compound universally effective against both Gram-negative and Gram-positive bacteria, as the lipophilic group facilitates membrane crossing in both types without compromising the DNA-binding mechanism that works across bacterial species.
Data Source
AI summary
The invention relates to pyrrolobenzodiazepines compounds (PBDs) and to pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular, to treat bacterial infections. The PBDs are compounds of formula (I): and salts and solvates thereof; wherein: dotted lines indicates the optional presence of a double bond; X, X1, X2, X3 and X4 are connecting functional groups; L is C1-12 alkylene; R4, R5 and R6 are independently selected from phenylene, cyclopentanylene, cyclohexanylene, 5- to 9-membered heteroarylene and 5- to 6-membered hetereocyclylene groups, and these groups are optionally substituted with up to three optional substituent groups; R7 is selected from N(C1-6 alkyl)(C1-6alkyl), 5- to 6-membered nitrogen-containing hetereocyclyl groups, a monosaccharide moiety and an amino monosaccharide moiety wherein these groups are optionally substituted; and R8 and R9 either together form a double bond, or are selected from H and OR14, or R8 is a prodrug moiety and R9 is OR14; m is 0 or 1; with the proviso that when X4 is C(O)NH then the up to three optional substituents of R7 are not selected from (CH2)k-CO2R12; with the proviso that when X4 is (CH2)tO then R4 is not phenylene, m is 1 and R6 is not a 5- to 9-membered heteroarylene; and with the proviso that when X4 is C(O)NH or NHC(O) that R4 and/or R6 is not 5- to 9-membered heteroarylene.