Antibacterial compounds

Details Antibacterial compounds Antibacterial compounds

2001-11-28

2003-06-03

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S085000, C546S086000, C546S087000

Reexamination Certificate

active

06573272

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutically active compounds which inhibit FabI and are useful for the treatment of bacterial infections.
BACKGROUND OF THE INVENTION
While the overall pathway of saturated fatty acid biosynthesis is similar in all organisms, the fatty acid synthase (FAS) systems vary considerably with respect to their structural organization. Vertebrates and yeast possess a FAS in which all the enzymatic activities are encoded on one or two polypeptide chains, respectively, and the acyl carrier protein (ACP) is an integral part of the complex. In contrast, in bacterial FAS, each of the reactions is catalyzed by a distinct, mono-functional enzyme and the ACP is a discrete protein. Therefore, there is considerable potential for the selective inhibition of the bacterial system by antibacterial agents.
FabI (previously designated EnvM) functions as an enoyl-ACP reductase (Bergler, et al, (1994),
J.Biol.Chem
. 269, 5493-5496) in the final step of the four reactions involved in each cycle of bacterial fatty acid biosynthesis. In this pathway, the first step is catalyzed by &bgr;-ketoacyl-ACP synthase, which condenses malonyl-ACP with acetyl-CoA (FabH, synthase III). In subsequent rounds, malonyl-ACP is condensed with the growing-chain acyl-ACP (FabB and FabF, synthases I and II, respectively). The second step in the elongation cycle is ketoester reduction by NADPH-dependent &bgr;-ketoacyl-ACP reductase (FabG). Subsequent dehydration by &bgr;-hydroxyacyl-ACP dehydrase (either FabA or FabZ) leads to trans-2-enoyl-ACP, which in turn is converted to acyl-ACP by NADH-dependent enoyl-ACP reductase (FabI). Further rounds of this cycle, adding two carbon atoms per cycle, eventually lead to palmitoyl-ACP (16C), where upon the cycle is stopped largely due to feedback inhibition of FabI by palmitoyl-ACP (Heath, et al, (1996),
J.Biol.Chem
. 271, 1833-1836). Thus, FabI is a major biosynthetic enzyme and is a key regulatory point in the overall synthetic pathway of bacterial fatty acid biosynthesis. Therefore, FabI is an ideal target for antibacterial intervention.
Studies have shown that diazaborine antibiotics inhibit fatty acid, phospholipid and lipopolysaccharide (LPS) biosynthesis and that the antibacterial target of these compounds is FabI. For example, derivative 2b18 from Grassberger, et al (1984)
J. Med Chem
27 947-953 has been reported to be a non-competitive inhibitor of FabI (Bergler, et al, (1994),
J.Biol.Chem
. 269, 5493-5496). Also, plasmids containing the FabI gene from diazaborine resistant
S. typhimurium
conferred diazaborine resistance in
E.coli
(Tumowsky, et al, (1989),
J.Bacteriol
., 171, 6555-6565). Furthermore, inhibition of FabI either by diazaborine or by raising the temperature in a FabI temperature sensitive mutant is lethal. These results demonstrate that FabI is essential to the survival of the organism (Bergler, et al, (1994),
J.Biol.Chem
. 269, 5493-5496).
Recent studies have shown that FabI is also the target for the broad spectrum antibacterial agent triclosan (McMurry, et al, (1998)
Nature
394, 531-532). A crystal structure of the
E. Coli
FabI complexed with NAD and triclosan shows that triclosan acts as a site-directed, very potent inhibitor of FabI by mimicking its natural substrate (Levy, et al, (1999)
Nature
398, 383-384). Ward, et al ((1999)
Biochem
. 38, 12514-12525) have shown that there is no evidence for the formation of a covalent complex between FabI and triclosan, which would be analogous to the diazaborines; triclosan differs from these compounds in that it is a reversible inhibitor of FabI. The structural data for the complex of FabI with NAD and triclosan provides important information about FabI as a therapeutic target.
Importantly, it has now been discovered that certain compounds are FabI inhibitors and have antibacterial activity, and, therefore, may be useful for the treatment of bacterial infections in mammals, particularly in man.
SUMMARY OF THE INVENTION
This invention comprises compounds of the formula (I), as described hereinafter, which inhibit FabI and are useful in the treatment of bacterial infections.
This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
This invention is also a method of treating bacterial infections by inhibiting FabI. In a particular aspect, the compounds of this invention are useful as antibacterial agents.
DETAILED DESCRIPTION
This invention comprises compounds of formula (I):
wherein:
R
1
is Ar or Het;
R
2
is H, C
1-6
alkyl or Ar—C
0-6
alkyl;
X is H, C
1-4
alkyl, OR′, SR′, C
1-4
alkylsulfonyl, C
1-4
alkylsulfoxyl, CN, N(R′)
2
, CH
2
N(R′)
2
, NO
2
, CF
3
, CO
2
R′, CON(R′)
2
, COR′, NR′C(O)R′, F, Cl, Br, I, or CF
3
S(O)
r
—;
R′ H, C
1-6
alkyl or Ar—C
0-6
alkyl; and
r is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
Also included in this invention are pharmaceutically acceptable addition salts and complexes of the compounds of this invention. In cases wherein the compounds of this invention may have one or more chiral centers, unless specified, this invention includes each unique racemic compound, as well as each unique nonracemic compound.
In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein
compounds may exist in tautomeric forms, such as keto-enol tautomers, such as
and
each tautomeric form is contemplated as being included within this invention, whether existing in equilibrium or locked in one form by appropriate substitution with R′. The meaning of any substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence.
Also included in this invention are prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
The compounds of formula (I) inhibit FabI. Inhibition of this enzyme is useful in the treatment of bacterial infections. Also, the compounds of this invention may be useful as antifungal agents. Additionally, the compounds may be useful in combination with known antibiotics.
With respect to formula (I):
Suitably, R
1
is phenyl, unsubstituted or substituted by methylenedioxy or by one to three substituents selected from the group consisting of C
1-4
alkyl, OR′, N(R′)
2
, F, Cl, Br, I, and CF
3
, in which R′ is H or C
1-6
alkyl.
Alternately, R
1
is benzimidazolyl or pyridinyl, unsubstituted or substituted by C
1-4
alkyl, OR′, N(R′)
2
, F, Cl, Br, I, and CF
3
, in which R′ is H or C
1-6
alkyl.
Suitably, R
2
is H, C
1-6
alkyl or phenyl-C
0-6
alkyl, wherein phenyl is unsubstituted or substituted by methylenedioxy or by one to three substituents selected from the group consisting of C
1-4
alkyl, OR″, CO
2
R′, N(R′)
2
, F, Cl, Br, I, and CF
3
, in which R′ is H or C
1-6
alkyl and R″ is H, C
1-6
alkyl or benzyl.
Suitably, X is H, C
1-4
alkyl, OR′, CN, N(R′)
2
, NO
2
, CF
3
, CO
2
R′, CON(R′)
2
, COR′, F, Cl, Br or I, in which R′ is H or C
1-6
alkyl.
Representative of the novel compounds of this invention are the compounds named in Examples 1-24 hereinafter.
Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of this invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in
Eur J. Biochem
., 158, 9 (1984).
C
1-4
alkyl as applied herein means an optionally substituted alkyl group of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. C
1-6
alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. C
0-4
alkyl and C
0-6
alkyl additionally indicates

Affiliated with

Also associated with

Rating

Antibacterial compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

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

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3147727