The pyrrolobenzodiazepines (PBDs) are a group of compounds some of which have been shown to be sequence-selective DNA minor-groove binding agents. The PBDs were originally discovered in Streptomyces species (1-5). They are tricyclic in nature, and are comprised of fused 6-7-5-membered rings that comprise an anthranilate (A ring), a diazepine (B ring) and a pyrrolidine (C ring) (3). They are characterized by an electrophilic N10═C11 imine group (as shown below) or the hydrated equivalent, a carbinolamine [NH—CH(OH)], or a carbinolamine alkyl ether ([NH—CH(OR, where R=alkyl)] which can form a covalent bond to a C2-amino group of guanine in DNA to form a DNA adduct (6).

The natural products interact in the minor groove of the DNA helix with excellent fit (i.e., good “isohelicity”) due to a right-handed longitudinal twist induced by a chiral C11a-position which has the (S)-configuration (6). The DNA adduct has been reported to inhibit a number of biological processes including the binding of transcription factors (7-9) and the function of enzymes such as endonucleases (10, 11) and RNA polymerase (12). PBD monomers (e.g., anthramycin) have been shown by footprinting (6), NMR (13, 14), molecular modeling (15) and X-ray crystallography (16) to span three base pairs and to have a thermodynamic preference for the sequence 5′-Pu-G-Pu-3′ (where Pu=purine, and G is the reacting guanine) (17) and a kinetic preference for Py-5-Py (where Py=Pyrimidine).
The ability of PBDs to form an adduct in the minor groove and crosslink DNA enables them to interfere with DNA processing and, hence, their potential for use as antiproliferative agents.
A number of monomeric PBD structures have been isolated from Streptomyces species, including anthramycin (18) the first PBD, tomamycin (19), and more recently usabamycin (20) from a marine sediment Streptomyces species in a marine sediment. This has led to the development of a large range of synthetic analogues which have been reviewed (1, 21). More recently, a number of monomeric PBD structures that are linked through their C8 position to pyrroles and imidazoles have been reported WO 2007/039752, WO 2013/164592 (22-27).
Infectious diseases are a leading cause of mortality and morbidity worldwide. The ability to treat effectively a range of bacterial infections rose dramatically following the introduction of penicillin and other antibiotics. However, the evolution of multidrug-resistant pathogens capable of rapid and efficient horizontal transmission of genes encoding antibiotic resistance determinants has diminished the therapeutic value of many frontline antibacterial therapeutic agents (28, 29). These multidrug-resistant pathogens are a serious threat to efforts to continue to keep infectious diseases under control.
WO 2005/085260 reported PBD dimers that had an effect on Gram-positive bacterial species, such as Staphylococcus aureus. The bactericidal activity of such PBD dimers against a range of Gram-positive pathogens have been reported (30, 31). More recently, WO 2013/164592 disclosed that conjugates of PBD with multi-aromatic species such as phenyls, pyrroles and imidazoles can be used against some drug resistant Gram-positive bacterial strains, such as methicillin resistant Staphylococcus aureus strains, see also (32). These conjugates failed to show any activity against Gram-negative bacteria.
PBD compounds have not been reported to have any useful effect against any Gram-negative bacterial species. It has been speculated that PBD compounds were not effective against Gram-negative bacterial species because the PBD compounds are unable to traverse the outer membrane of Gram-negative bacterial species (28). This is significant as increasing multidrug resistance has been a particular problem with Gram-negative pathogens, such as Pseudomonas aeruginosa and Acinetobacter baumannii. 
In addition, many PBD compound have a high degree of cytotoxicity which has rendered them unattractive for use as antibacterial agents.
The present invention seeks to alleviate these problems associated with the prior art.
USPTO Backgrounds
USPTO Backgrounds