Heterocyclic compounds and uses thereof as d-alanyl-d-alanine ligase inhibitors

a technology of d-alanyl-d-alanine ligase and heterocyclic compounds, which is applied in the field of heterocyclic compounds, can solve the problems of increasing the resistance of organisms to the various exogenous factors, chronic infection or even death, and complex pathogenic processes by which microorganisms elicit adverse effects on subjects, etc., and achieves broad spectrum activity, reduced side effects, and different selectivity profiles

Inactive Publication Date: 2008-04-17
PLIVA D D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0041] The invention can provide several advantages over the existing methods of treatment. For example, the compounds of the invention can bind to the ATP-binding site of the D-Ala-D-Ala ligase enzyme with high specificity and are shown to be competitive with ATP in biochemical assays. Some compounds described in this invention have their protein-interacting functional groups situated so as to be able to also bind to one or both of the D-alanine binding sites of D-Ala-D-Ala ligase. These types of new compounds (bisubstrate analogs) may have further enhanced selectivity and potency directly associated with the ability to bridge the ATP site and D-Ala site.
[0043] Moreover, some compounds of the invention may have several chemical and pharmacological advantages over existing compounds used in treating bacterial infections. These advantages may include both chemical stability and pharmacological stability, as well as potency, different resistance profiles, different selectivity profiles, and decreased side-effects. The new compounds' activity and ability to cross bacterial cell membranes also makes them suitable for use as antibiotic drugs. The invention also envisions veterinary uses for the treatment of infections in fish, fowl, livestock, other food animals, sports animals, and companion animals.
[0044] The compounds of the invention have displayed potent broad spectrum activity against a representative panel of microorganisms, including E. coli, S. aureus, S. pneumoniae, H. influenzae, and others. Broad spectrum activity is also inferred from the close sequence homology in the D-Ala-D-Ala ligases of fifty-one representative, but evolutionarily diverse, microorganisms representative of all bacteria. Nonetheless, individual compounds do have greater activity against specific bacteria, creating opportunities for the development of selective and specific narrow-spectrum agents as well.

Problems solved by technology

The pathogenic processes by which microorganisms elicit their adverse effects on subjects are generally complex and require a defined sequence of events that implicate multiple microbial components.
If left unchecked, the proliferation of organisms can impair the subject, resulting in chronic infection, or even death.
Over time, and due in part to injudicious use of existing antibiotic treatment regimens, organisms are becoming increasingly resistant to the various exogenous factors available.
Further, there is a serious decrease in susceptibility of E.

Method used

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  • Heterocyclic compounds and uses thereof as d-alanyl-d-alanine ligase inhibitors
  • Heterocyclic compounds and uses thereof as d-alanyl-d-alanine ligase inhibitors
  • Heterocyclic compounds and uses thereof as d-alanyl-d-alanine ligase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Ligase Inhibitors

[0136]

N7-Methyl-N-7-(1-naphthalen-1-yl-propyl)-pyrimido[4,5-d]pydrimidine-2,4,7-triamine

[0137] Compound 1: To a solution of 4.25 g (27.2 mmol) naphthaldehyde in 30 ml dry ether in ice water bath was slowly added 13 ml of ethylmagnesium bromide, 3 M in ether. The mixture was stirred for another 30 min at room temperature and then quenched by adding 40 ml of 1N HCl solution. The organic layer was washed with water (20 ml), sat. sodium bicarbonate (20 ml×2), brine (20 ml) and then dried over anhydrous sodium sulfate. Evaporation of the organic solvent gave a crude product 1 which was directly used for the next step of the reaction without further purification.

[0138] Compound 2: The crude product 1 was dissolved in 30 ml acetone and to the resulting mixture, bathed in an ice water bath, was slowly added Jone's reagent until the brown color persisted. The solution was further stirred for 15 min at room temperature and then 5 ml of isopropanol was added. A...

example 2

D-Ala-D-Ala-Ligase Ki Determination

[0181] The synthetic analogs of Example 1 were dissolved in dimethylsulfoxide (DMSO) at a concentration of 100 mM on the day of screening, using a vortex mixer and sonication if necessary for dissolution. The solutions were kept at room temperature until screening was completed.

[0182] A 10 mM NADH (Sigma) stock solution was prepared freshly on the day of screening by dissolving 32 μmol NADH in 3.2 ml double-distilled water. The NADH solution was kept on ice. Stock solutions containing 50 mM phosphoenolpyruvate (PEP; Sigma), 500 μM HERMES, 30 mM adenosine triphosphate (ATP; Sigma), 200 mM D-alanine (Sigma), and 4× core buffer (i.e., 400 mM Hepes, 40 mM magnesium chloride, and 40 mM potassium chloride), were also stored on ice. A stock solution of pyruvate kinase / lactate dehydrogenase (PK / LDH) was also obtained from Sigma.

[0183] Table of Final concentrations are dependent on the type of screening:

ANALOGS' %ANALOGS' Ki ANDANALOGS' KiINHIBITIONMOD...

example 3

Determination of Ki of Analogs

[0185] For each set of test compounds, two 96-well plates were used: an inhibitor plate and an enzyme plate. The test compounds correspond to rows A-G of the plates. Adenosine (Sigma) dissolved in DMSO, used as a control, corresponds to row H of each plate.

[0186] The enzyme solution was allowed to equilibrate to 25° C.

[0187] Dilutions were prepared in the inhibitor plate as follows: 50 μl DMSO was added to each well of columns 1-11, rows A-G, of the inhibitor plate. 50 μl DMSO were added to each well of columns 1-11, row H. 100 μl of the 100 mM test solutions were added to column 12, rows A-G (i.e., the first compound in row A, the second compound in row B, and so on). 100 μl of a 100 mM Adenosine solution was added to column 12, row H.

[0188] 50 μl of the test solution was transferred from column 12 in each row to column 11 of the a same row, mixing the solution with the DMSO. 50 μl of solution was then transferred from column 11 in each row to colu...

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Abstract

The invention is based on the discovery of a new class of heterocyclic compounds having, for example, antibacterial properties. The D-Ala-D-Ala ligase enzyme is a critical pathway enzyme in the bacterial cell-wall synthesis. The compounds can bind to and inhibit the enzyme D-Ala-D-Ala ligase. The new compounds' activity combined with their ability to cross bacterial cell membranes makes them suitable for use as antibacterial drugs or other antibacterial applications.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application No. 60 / 301,685, filed Jun. 28, 2001, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] This invention relates to heterocyclic compounds and to their use, for example, in the prophylaxis and or medical treatment of bacterial infections and their use, for example, as antiseptics, sterilizants, or disinfectants. BACKGROUND OF THE INVENTION [0003] The pathogenic processes by which microorganisms elicit their adverse effects on subjects are generally complex and require a defined sequence of events that implicate multiple microbial components. If left unchecked, the proliferation of organisms can impair the subject, resulting in chronic infection, or even death. It is frequently necessary to bolster host defense mechanisms with exogenous factors such as antibiotics to aid clearance of the infecting organism from the subject. [0004] Over t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/495A61P33/00C07D475/04C12N9/99A61K31/519A61K31/525A61P31/04C07D401/12C07D471/04C07D475/08C07D487/02C07D487/04C07D519/00
CPCC07D401/12C07D487/04C07D475/08C07D471/04A61P31/04A61P33/00
Inventor MOE, SCOTT T.ALA, PAUL J.PEROLA, EMANUELEFAERMAN, CARLOS H.CLEMENT, JACOB J.ALI, JANID A.WILL, PAULMARCHESE, SALVATORE A.MAGEE, ANDREW S.GAZZANIGA, JOHN V.FARADAY, CHRISTOPHERNAVIA, MANUEL A.CONNELLY, PATRICK R.
Owner PLIVA D D
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