LpxC Inhibitors as Effective Therapy Against Multidrug Resistant Bacterial Infections

The invention in this patent application relates to 1,2-chthydro-3H-pyrrolo[1,2-c]imidazol-3-one derivatives represented generally by formula (I), which are LpxC inhibitors. They possess antimicrobial activities against a variety of human and veterinary pathogens, especially Gram-negative aerobic and anaerobic bacteria and may potentially provide effective treatment against multidrug resistant bacterial infections. In the recent years several multidrug resistant bacteria strains, particularly the Gram-negative organisms, have emerged so that it is now difficult or sometimes impossible to treat some of these bacterial infections. A main reason for such difficulty is the lack of newly developed novel agents to replace those old ones that have been in use for decades. Therefore, there exists an urgent need to develop new antibacterial agents with new mechanisms of action and identify new therapeutic targets capable of combating infections with bacteria particularly Gram-negative drug resistant bacteria. Studies on Gram-negative bacteria have identified charged lipopolysaccharide (LPS) molecules in the bacteria's cell wall membrane. The hydrophobic anchor molecule of LPS is a glucosamine derivative called Lipid A. The LPS membrane functions as a protective mechanism to block the entry of hydrophobic molecules into the bacteria. This function is essential for the survival of the Gram-negative bacteria and consequently it presented a potential new therapeutic target to develop a novel treatment for bacterial infections. Therefore, inhibitors of the bacterial enzymes used in the biosynthesis of the Lipid A may be effective novel antimicrobial agents to treat infections caused by Gram-negative resistant bacteria. One of the bacterial enzymes that received significant attention is LpxC, a zinc-dependent deacetylase, which catalyzes the deacetylation of UDP-3-O-(R-3-hydroxymyristoyl)GlcNAc, a key step in the biosynthesis of Lipid A. Thus far, the researchers in this area have introduced several new inhibitors of LpxC that displayed promising antimicrobial activities. The compounds described in this patent application are LpxC inhibitors and may potentially provide a needed treatment for multidrug resistant bacterial infections.