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AssigneeThe Trustees of Columbia University in the City of New York
InventorsChristina Kabbash, Samuel C. Silverstein, Howard A. Shuman, John S. Blanchard
Estimating the term…
The present invention provides for a method of inhibiting activity of an enoyl reductase enzyme in a cell which comprises contacting the cell with a compound having the structure: 1 wherein each of R1, R2, R3, R4, R5 and R6 is independently selected from the group consisting of: —H, —F, —Cl, —Br, —I, —OH, —OR, —CN, —COR7, —SR7, —N(R7)2, —NR7—COR8, —NO2, —(CH2)p —OR7, —COSR7, —COOH, —CONH2, —NH2, a straight chain or branched, substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, thioalkyl, methylene thioalkyl, acyl, phenyl, substituted phenyl, or heteroaryl; wherein L is alternatively —N—, —S—, —O— or —C—; wherein R7 is independently selected from the group consisting of —H, —F, —Cl, —Br, —I, —OH, —CN, —COH, —SH2, —NH2, —NHCOH, —(CH2)pOH, a straight chain or branched, substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, thioalkyl, methylene thioalkyl, acyl, phenyl, substituted phenyl, or heteroaryl; wherein A is selected from the group consisting of —N2—, —NH—, —C═C═CH2—, —C≡C—C2HOH—, —C≡C—CH2—, —CH2—CH2 —O—, —CH2—CH2—CH2—O—, —S—, —S(═O)2—, —C═O—, —C═O—O—, —NH—C═O—, —C═O—NH—; wherein Q is independently an integer from 1 to 10, or if Q is 1, A may be a (C1-C10)-alkyl chain, (C1-C10)-alkenyl chain or (C1-C10)-alkynyl chain which is branched or unbranched, substituted or unsubstituted and is optionally interrupted 1 to 3 times by —O— or —S— or —N—; wherein X is —CO2—, —CH═CH3, phenyl, substituted phenyl, or heteroaryl, —O-phenyl(CH3)2, —C(CH2)2—CO—NH2, —C(CH2)2—COOH; or a pharmaceutically acceptable salt or ester thereof, which compound is present in a concentration effective to inhibit activity of the enzyme.
A method of inhibiting activity of an enoyl reductase enzyme in a cell which comprises contacting the cell with a compound having the structure:
A method of selecting a compound which inhibits the enzymatic activity of enoyl reductase which comprises:
A method of selecting a compound which inhibits the enzymatic activity of enoyl reductase which comprises:
A method for inhibiting growth of a bacterium which consists essentially of contacting the bacterium with a compound having the structure:
A method for alleviating the symptoms of a bacterial infection in a subject which comprises administering to the subject an amount of a compound having the structure:
A method of altering (inhibiting or enhancing) a biochemical pathway of fatty acid synthesis in a bacterium which comprises contacting the bacterium with a compound having the structure
A method of inhibiting activity of an enoyl reductase enzyme in a cell which comprises contacting the cell with a compound having the structure:
Dependencies are inferred from the claim text.
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Measuring or testing processes involving enzymes, nucleic acids or microorganisms ; Compositions therefor; Processes of preparing such…
Medicinal preparations containing organic active ingredients
Ethers or acetals: having an ether linkage to aromatic ring nuclear carbon
Amides, e.g. hydroxamic acids: having aromatic rings, e.g. colchicine, atenolol, progabide
Term end not estimated
Throughout this application, various publications are referenced by a number in brackets. Full citations for these publications may be found listed by number at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Gemfibrozil (GFZ) is a compound that has been utilized as a drug for increasing intracellular accumulation of hydrophilic anionic agents (U.S. Pat. No. 5,422,372, issued Jun. 6, 1995) and as a lipid regulating composition (U.S. Pat. No. 4,859,703, issued Aug. 22, 1989). Gemfibrozil has been shown to be effective in increasing the amount of cholesterol excreted in to bile. (Ottmar Leiss et al., Metabolism, 34(1):74-82 (1985)). Gemfibrozil is described in U.S. Pat. No. 3,674,836 and in The Merck Index, 11 ed., Merck & Co., Inc. Rahway, N.J. 1989; #4280. Gemfibrozil, a drug which therapeutically lowers triglycerides and raises HDL-cholesterol levels, previously has not been reported to have antimicrobial activity. (Brown, 1987; Oliver et al., 1978 and Palmer et al., 1978).
The present invention provides for a method of inhibiting activity of an enoyl reductase enzyme in a cell which comprises contacting the cell with a compound having the structure: 2
FIG. 1. Comparison of fatty acids synthesized by E. coli [5], and L. pneumophila [6, 7]. The number immediately preceding the colon refers to the number of carbons, the number following the colon refers to the number of double bonds, the superscript number refers to the location of the double bonds. a=anteiso; i=iso; OH=hydroxy.
FIG. 2. Fatty acid synthesis in E. coli. Initiation of fatty acid synthesis occurs with the condensation of acetyl-CoA with malonyl-ACP, or, conversion of acetyl-CoA to acetyl-ACP prior to condensation with malonyl-ACP. Subsequent elongation occurs though the sequential addition of two carbon units using malonyl-ACP as the donor. Elongation occurs through a four step process in which the first step, condensation, is mediated by β-ketoacylsynthase (FabB, FabF, FabH); the second step, reduction, is mediated by β-ketoacyl reductase (FabG); the third step, dehydration, is mediated through β-hydroxyacyl dehydratase (Fab Z); and the fourth and final step, reduction, is mediated through enoyl reductase (FabI). Unsaturated fatty acids are synthesized by the diversion of β-hydroxydecanol-ACP to FabA which catalyzes the formation of a double bond and then returns the unsaturated fatty acid to the cycle. The double lines indicate points where compounds act to inhibit fatty acid synthesis. The compounds are: DZB, diazoborines; ETH, ethionamide; INH, isoniazid; CER, cerulenin; TLM, thiolactomycin; NAG, 3-decenoyl-N-acetylcysteamine.
FIG. 3. GFZ inhibits intracellular multiplication of L. pneumophila in phorbol myristate acetate-differentiated HL-60 cells. HL-60 cells were differentiated into macrophages by treatment with PMA for 48 hours, plated as a monolayer in the wells of a microtiter plate, and synchronously infected with L. pneumophila (final multiplicity of infection of 0.01). After 2 hrs, the cells were washed to remove extracellular bacteria, overlaid with fresh RPMI-2 mM GLN-10% NHS without or with GFZ (100 μg/ml), and incubated at 37° C. At the times indicated, the cells and medium were harvested and assayed for L. pneumophila. Illustrated is an experiment typical of three performed. Each point is the average of three separate wells (+/−) the SEM.
The present invention provides for a method of inhibiting activity of an enoyl reductase enzyme in a cell which comprises contacting the cell with a compound having the structure: 3
wherein each of R1 R2, R3, R4, R5 and R6 is independently selected from the group consisting of: —H, —F, —Cl, —Br, —I, —OH, —OR7, —CN, —COR7, —SR7, —N(R7)2, —NR7—COR8, —NO2, —(CH2)p—OR7, —COSR7, —COOH, —CONH2, —NH2, a straight chain or branched, substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, thioalkyl, methylene thioalkyl, acyl, phenyl, substituted phenyl, or heteroaryl;
wherein L is alternatively —N—, —S—, —O— or —C—;