Hydroxamic acid derivatives as antibacterials

Details Hydroxamic acid derivatives as antibacterials Hydroxamic acid derivatives as antibacterials

2000-11-15

2002-08-27

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

Reexamination Certificate

active

06441042

ABSTRACT:

This invention relates to the use of hydroxamic acid derivatives as antibacterial agents.
BACKGROUND TO THE INVENTION
In general, bacterial pathogens are classified as either Gram-positive or Gram-negative. Many antibacterial agents (including antibiotics) are specific against one or other Gram-class of pathogens. Antibacterial agents effective against both Gram-positive and Gram-negative pathogens are therefore generally regarded as having broad spectrum activity.
Many classes of antibacterial agents are known, including the penicillins and cephalosporins, tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The fundamental mechanisms of action of these antibacterial classes vary.
Bacterial resistance to many known antibacterials is a growing problem. Accordingly there is a continuing need in the art for alternative antibacterial agents, especially those which have mechanisms of action fundamentally different from the known classes.
Amongst the Gram-positive pathogens, such as Staphylococci, Streptococci, Mycobacteria and Enterococci, resistant strains have evolved/arisen which makes them particularly difficult to eradicate. Examples of such strains are methicillin resistant
Staphylococcus aureus
(MRSA), methicillin resistant coagulase negative Staphylococci (MRCNS), penicillin resistant
Streptococcus pneumoniae
and multiply resistant
Enterococcus faecium.
Pathogenic bacteria are often resistant to the aminoglycoside, &bgr;-lactam (penicillins and cephalosporins), and chloramphenicol types of antibiotic. This resistance involves the enzymatic inactivation of the antibiotic by hydrolysis or by formation of inactive derivatives. The &bgr;-lactam (penicillin and cephalosporin) family of antibiotics are characterised by the presence of a &bgr;-lactam ring structure. Resistance to this family of antibiotics in clinical isolates is most commonly due to the production of a “penicillinase” (&bgr;-lactamase) enzyme by the resistant bacterium which hydrolyses the &bgr;-lactam ring thus eliminating its antibacterial activity.
Recently there has been an emergence of vancomycin-resistant strains of enterococci (Woodford N. 1998 Glycopeptide-resistant enterococci: a decade of experience. Journal of Medical Microbiology. 47(10):849-62). Vancomycin-resistant enterococci are particularly hazardous in that they are frequent causes of hospital based infections and are inherently resistant to most antibiotics. Vancomycin works by binding to the terminal D-Ala-D-Ala residues of the cell wall peptidioglycan precursor. The high-level resistance to vancomycin is known as VanA and is conferred by a genes located on a transposable element which alter the terminal residues to D-Ala-D-lac thus reducing the affinity for vancomycin.
In view of the rapid emergence of multidrug-resistant bacteria, the development of antibacterial agents with novel modes of action that are effective against the growing number of resistant bacteria, particularly the vancomycin resistant enterococci and &bgr;-lactam antibiotic-resistant bacteria, such as methicillin-resistant
Staphylococcus aureus,
is of utmost importance.
BRIEF DESCRIPTION OF THE INVENTION
This invention is based on the finding that certain hydroxamic acid derivatives have antibacterial activity, and makes available a new class of antibacterial agents. The inventors have found that the compounds with which this invention is concerned are antibacterial with respect to a range of Gram-positive and Gram-negative organisms.
Although it may be of interest to establish the mechanism of action of the compounds with which the invention is concerned, it is their ability to inhibit bacterial growth which makes them useful. However, it is presently believed that their antibacterial activity is due, at least in part, to intracellular inhibition of bacterial polypeptide deformylase (PDF) enzyme.
Bacterial polypeptide deformylases (PDF) (EC 3.5.1.31), are a conserved family of metalloenzymes (Reviewed: Meinnel T, Lazennec C, Villoing S, Blanquet S, 1997, Journal of Molecular Biology 267, 749-761) which are essential for bacterial viability, their function being to remove the formyl group from the N-terminal methionine residue of ribosome-synthesised proteins in eubacteria. Mazel et al. (EMBO J. 13(4):914-923, 1994) have recently cloned and characterised an
E. coli
PDF. As PDF is essential to the growth of bacteria and there is no eukaryotic counterpart to PDF, Mazel et al. (ibid), Rajagopalan et al. (J. Am. Chem. Soc. 119:12418-12419, 1997) and Becker et al., (J. Biol Chem. 273(19):11413-11416, 1998) have each proposed that PDF is an excellent anti-bacterial target.
The natural antibiotic actinonin (see for example J.C.S Perkin I, 1975, 819) is a hydroxamic acid derivative of Structure (A):
In addition, various structural analogues of actinonin have also been shown to have antibacterial activity (see for example Broughton et al. (Devlin et al. Journal of the Chemical Society. Perkin Transactions 1 (9):830-841, 1975; Broughton et al. Journal of the Chemical Society. Perkin Transactions 1 (9):857-860, 1975).
Hydroxamic acid derivatives are also known in the field of matrix metalloproteinase (MMP) inhibition. Many examples of the class have been synthesised and their MMP inhibitory properties reported. A smaller number have been reported to be active in animal models of diseases mediated by MMPs, for example various cancers and rheumatoid arthritis. For reviews of the patent literature on hydroxamate MMP inhibitors, see for example Beckett, Exp. Opin. Ther. Patents (1996) 6, 1305-1315, and Beckett & Whittaker, Exp. Opin. Ther. Patents (1998), 8(3), 259-282, and the documents cited therein.
DESCRIPTION OF THE INVENTION
According to the present invention there is provided the use of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof in the preparation of an antibacterial composition:
wherein:
R
1
represents hydrogen, or C
1
-C
6
alkyl, C
1
-C
6
alkyl substituted by one or more halogen atoms, amino, hydroxy, or C
1
-C
6
alkoxy;
R
2
represents a group R
10
—(X)
n
—(ALK)
m
— wherein
R
10
represents hydrogen, or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may be unsubstituted or substituted by (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, hydroxy, mercapto, (C
1
-C
6
)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, —COOH, —CONH
2
, —COOR
A
, —NHCOR
A
, —CONHR
A
, —NHR
A
, —NR
A
R
B
, or —CONR
A
R
B
wherein R
A
and R
B
are independently a (C
1
-C
6
)alkyl group, and ALK represents a straight or branched divalent C
1
-C
6
alkylene, C
2
-C
6
alkenylene, or C
2
-C
6
alkynylene radical, and may be interrupted by one or more non-adjacent —NH—, —O— or —S—linkages,
X represents —NH—, —O— or —S—, and
m and n are independently 0 or 1; and
A represents (i) a group of formula (IA), (IB), (IC) or (ID)
 wherein:
R
3
represents hydrogen or C
1
-C
6
alkyl and R
4
represents the side chain of a natural or non-natural alpha amino acid or R
3
and R
4
when taken together with the nitrogen and carbon atoms to which they are respectively attached form an optionally substituted saturated heterocyclic ring of 5 to 8 atoms which ring is optionally fused to a carbocyclic or second heterocyclic ring,
R
5
and R
6
, independently represent hydrogen, or optionally substituted C
1
-C
8
. alkyl, cycloalkyl, aryl, aryl(C
1
-C
6
alkyl), heterocyclic, or heterocyclic(C
1
-C
6
alkyl), or R
5
and R
6
when taken together with the nitrogen atom to which they are attached form an optionally substituted saturated heterocyclic ring of 3 to 8 atoms which ring is optionally fused to a carbocyclic or second heterocyclic ring, and
R
7
represents hydrogen, C
1
-C
6
alkyl, or an acyl group.
PROVIDED THAT (a) R
5
and R
6
taken together with the nitrogen atom to which they are attached do not form an optionally substitut

Affiliated with

Also associated with

Rating

Hydroxamic acid derivatives as antibacterials does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Hydroxamic acid derivatives as antibacterials, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hydroxamic acid derivatives as antibacterials will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2876269