PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
LpxC Inhibitors as Effective Therapy Against Multidrug Resistant Bacterial Infections Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
1,2-Dihydro-3H-pyrrolo[1,2-C]imidazol-3-one Derivatives and Their Use as Antibacterial Agents
Patent Application Number: Priority Application:
WO 2015/132228 A1 EP 14157636.3
Inventors:
Chapoux, G.; Gauvin, J.-C.; Panchadd, P.; Specklin, J.-L.; Surivet, J.-P.; Schmitt, C.
Assignee Company:
Actelion Pharmaceuticals Ltd.; Gewerbestrasse 16, CH-4123 Allschwil (CH)
Disease Area:
Multidrug resistant Gram-negative
Publication date: Priority date:
Biological Target:
11 September 2015 4 March 2014
The bacterial enzyme UDP-(3-O-(R-3-hydroxymyristoyl))N-acetylglucosamine deacetylase (LpxC)
bacterial infections
The invention in this patent application relates to 1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one derivatives represented generally
Summary:
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-3O-(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. Important Compound Classes:
Received:
r XXXX American Chemical Society
A
October 6, 2015
dx.doi.org/10.1021/acsmedchemlett.5b00391 | ACS Med. Chem. Lett. XXXX, XXX, 000–000
ACS Medicinal Chemistry Letters Key Structures:
PATENT HIGHLIGHT
The inventors described the synthesis and structures of 83 examples of formula (I) including the following representative examples (structures were produced from the chemical names using ChemDraw):
Biological Assay:
In vitro assays • Bacterial growth minimal inhibitory concentrations All invention compounds were tested against several Gram-positive and Gram-negative bacteria. K. pneumoniae A-651 is a multiply resistant strain (in particular quinolone-resistant), while E. coli ATCC25922 and P. aeruginosa ATCC27853 are quinolone-sensitive strains.
Biological Data:
Antibacterial activities are reported as minimal inhibitory concentrations (MICs) in mg/L. The results obtained from the above representative examples are listed in the following table:
Recent Review Article:
1. Keating, T. A.; Lister, T.; Verheijen, J. C. Pharm. Pat. Anal. 2014, 3 (1), 87 112. 2. Zhang, J.; Zhang, L.; Li, X.; Xu, W. Curr. Med. Chem. 2012, 19 (13), 2038 2050. 3. Barb, A. W.; Zhou, P. Curr. Pharm. Biotechnol. 2008, 9 (1), 9 15.
’ AUTHOR INFORMATION Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
B
dx.doi.org/10.1021/acsmedchemlett.5b00391 |ACS Med. Chem. Lett. XXXX, XXX, 000–000
