Inhibitors of bacterial nad synthetase
OwnerWayne J. Brouillette, Donald Muccio +8inventors
InventorsWayne J. Brouillette, Donald Muccio, Mark J. Jedrzejas, Christie G. Brouillette, Yancho Devedjiev, Walter Cristofoli, Lawrence J. DeLucas, Jose Gabriel Garcia, Laurent Schmitt, Sadanandan E. Velu
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Abstract
The present invention provides methods of synthesizing and screening inhibitors of bacterial NAD synthetase enzyme, compounds thereof, and methods of treating bacterial and microbial infections with inhibitors of bacterial NAD synthetase enzyme.
Claims262
A bacterial NAD synthetase enzyme inhibitor compound of the structure:
- 280 281 282 283 284 285 286 287 288 289 290
A bacterial NAD synthetase enzyme inhibitor compound, having Structure 2:
- 291
- wherein n is an integer of from 1 to 12, R1-R7 each, independently, is an H, an unsubstituted or a substituted cyclic or aliphatic group, or a branched or an unbranched group, and wherein the linker is a cyclic or aliphatic, branched or an unbranched alkyl, alkenyl, or an alkynyl group and wherein the linker may also contain heteroatoms.
A bacterial NAD synthetase enzyme inhibitor compound, having Structure 4:
- 292
- wherein X is a C, N, O or S within a monocyclic or bicyclic moiety, A and B represent the respective sites of attachment for the linker, n is an integer of from 1 to 12, R1-R7 each, independently, is an H, an unsubstituted or a substituted cyclic group, or an aliphatic group, or a branched or an unbranched group, and the linker is a saturated or unsaturated cyclic group or an aliphatic branched or unbranched alkyl, alkenyl or alkynyl group, and wherein the linker may also contain heteroatoms.
A bacterial NAD synthetase enzyme inhibitor compound of Structure 6:
- 293
- wherein X is C, N, O or S, Y is C, N, O, S, carboxy, ester, amide, or ketone, A and B represent the respective sites of attachment for a linker, n is an integer of from 1 to 12, and R1-R7 each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, and the linker is a saturated or unsaturated cyclic or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.
A compound of Structure 132:
- 308
- wherein n is an integer of from 1 to 12 and R is 5-H, 6-CF3, 5-CH3, 5,7-diF, 5,7-diNO2, 5-Butyl, 5-iPropyl, 5-Phenyl, 5-NO2, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF3, 5-COCH3, 5-OCH3, 5-COOCH3 or 5-COOH.
A method of treating or preventing a microbial infection in a mammal comprising administering to the mammal a treatment effective or treatment preventive amount of a bacterial NAD synthetase enzyme inhibitor compound.
A method of killing a prokaryote with an amount of prokaryotic NAD synthetase enzyme inhibitor to reduce or eliminate the production of NAD whereby the prokaryote is killed.
A method of decreasing prokaryotic growth, comprising contacting the prokaryote with an amount of a prokaryotic NAD synthetase enzyme inhibitor effective to reduce or eliminate the production of NAD whereby prokaryotic growth is decreased.
A disinfectant compound wherein the compound comprising a bacteria] NAD synthetase enzyme inhibitor.
A method of disinfecting a material contaminated by a microbe, comprising contacting a contaminated material with a bacterial NAD synthetase enzyme inhibitor compound in an amount sufficient to kill or deactivate the microbe.
A method of making a bacterial NAD synthetase inhibitor compound comprising the steps of:
- a. alkylating 5-nitroindole with 6-bromohexyl acetate to form a 6-[N-(5-nitroindolyl)] hexyl acetate;
- b. hydrolyzing the 6-[N-(5-nitroindolyl)] hexyl acetate to form N-(5 nitroindolyl)hexan-1-ol;
- c. esterifying the 6[-N-(5-nitroindolyl)]hexan-1-ol with nicotinic acid to form N-(5-nitroindolyl)hexyl nicotinate;
- and
- d. N-methylating the 6[-N-(5-nitroindolyl)]hexyl nicotinate.
A method of making a bacterial NAD synthetase inhibitor compound comprising the steps of:
- a. alkylating 5-nitroindole with bromoalkyl acetate wherein the indole alkyl acetate is converted to indole alkyl alcohol;
- b. reacting the indole alkyl alcohol with the appropriate reagent to form an indole alkyl ester;
- and
- c. N-methylating the indole alkyl ester.
A method of making a bacterial NAD synthetase inhibitor compound comprising the steps of:
- a. reacting indole carboxylic acid with the appropriate reagent to provide an indole carboxylate methyl ester or an indole benzyl carboxylate ester;
- b. N-alkylating the indole carboxylate methyl ester or the indole carboxylate benzyl ester with bromoalkyl acetate;
- c. reacting the material from step b above with the appropriate reagent to form an indolealkyl alcohol;
- d. coupling the indolealkyl alcohol with an aromatic amine;
- and
- e. reacting the indolealkyl alcohol with the appropriate reagent to convert the methyl or benzyl indolecarboxylate to the respective indole carboxylic acids.
A method of making a bacterial NAD synthetase inhibitor compound comprising the steps of:
- a. brominating an aniline with N-bromosuccinimide to form a 2-bromo-R1-substituted-aniline or a 2-bromo-R2-substituted-aniline;
- b. reacting the 2-bromo-R1-substituted-aniline or the 2-bromo-R2-substituted-aniline using a Heck coupling reaction to form an alkyne-substituted aniline;
- c. reacting the alkyne-substituted aniline using a cyclization reaction to form an indole alcohol;
- d. quaternizing the indole alcohol with an amine;
- e. reacting the indole alcohol with methansulfonyl chloride to provide an indole mesylate;
- and
- f. reacting the indole mesylate with a carboxylic acid to form an indole ester.
A method of making a bacterial NAD synthetase inhibitor compound comprising the steps of:
- a. brominating an aniline with N-bromosuccinimide to form a 2-bromo-R1-substituted-aniline or a 2-bromo-R2-substituted-aniline;
- b. reacting the 2-bromo-R1-substituted-aniline or a 2-bromo-R2-substituted-aniline using a Heck coupling reaction to form an alkyne-substituted aniline;
- c. reacting the alkyne-substituted aniline using a cyclization reaction to form an indole alcohol;
- d. quaternizing the indole alcohol with an amine;
- e. reacting the indole alcohol with triflouromethylsulfonic anhydride to provide a triflate;
- and
- f. reacting the indole triflate with an amine to form an indole alkylammonium product.
A method of making a bacterial NAD synthetase inhibitor compound comprising the steps of:
- a. alkylating a phenol with 7-bromo-1-heptanol to provide 7-(phenyloxy)-1-heptanol;
- b. mesylating 7-(phenyloxy)-1-heptanol to provide 7-(phenyloxy)-1-heptyl methanesulfonate;
- c. esterifying 7-(phenyloxy)-1-heptyl-methanesulfonate to provide 7-(phenyloxy)-1-heptyl nicotinate;
- and
- d. n-methylating 7-(phenyloxy)-1-heptyl nicotinate to provide [7-(phenyloxy)-1-heptyl-(N-methyl) nictotinate] iodide.
A method of generating a library comprising at least one bacterial NAD synthetase enzyme inhibitor compound comprising the steps of:
- a. obtaining the crystal structure of a bacterial NAD synthetase enzyme;
- b. identifying one or more sites of catalytic activity on the NAD synthetase enzyme;
- c. identifying the chemical structure of the catalytic sites on the NAD synthetase enzyme;
- d. selecting one or more active molecules that will demonstrate affinity for at least one of the catalytic sites on the NAD synthetase enzyme;
- e. synthesizing one or more dimeric compounds comprised of at least one active molecule compound wherein the active molecule compound are joined by means of n linker compounds and wherein n is an integer of from 1 to 12, and
- f. screening the one or more compounds for bacterial NAD synthestase inhibitor activity.
The method of claim<234 wherein a software program that predicts the binding affinities of molecules to proteins is utilized in the active molecule selection step.
A method for the in vitro screening a compound for bacterial NAD synthetase enzyme inhibitory activity comprising the steps of:
- a. preparing a bacterial NAD synthetase enzyme solution from pure bacterial NAD synthetase enzyme mixed with a suitable buffer;
- b. contacting the bacterial NAD synthetase enzyme solution with a test compound;
- and
- c. measuring the rate of the enzyme-catalyzed reaction between the NAD synthetase enzyme and the test compound,
- wherein the rate of the enzyme catalyzed reaction comprises a measure of bacterial NAD synthetase enzyme inhibitory activity.
A bacterial NAD synthetase enzyme inhibitor compound of Structure 7:
- 350
- wherein X is C, N, O or S, Y is C, N, O, S, carboxy, ester, amide, or ketone, A and B represent the respective sites of attachment for a linker, n is an integer of from 1 to 12, and R1-R6 each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, and the linker is a saturated or unsaturated cyclic or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.
A bacterial NAD synthetase enzyme inhibitor compound of the structure:
- 351 352 353 354 355 356 357 358 359 360 361 362 363 364
A bacterial NAD synthetase enzyme inhibitor of the formula:
- 365 366 367 368
Dependencies are inferred from the claim text.