US2003125337A1PendingUtilityA1
Inhibitors of multidrug transporters
Est. expiryDec 4, 2018(expired)· nominal 20-yr term from priority
Inventors:Penelope MarkhamDebbie MulhearnAlexander NeyfakhDavid CrichMohamad R. JaberMichael E. Johnson
A61P 31/10A61K 31/403A61K 31/404A61P 31/04A61K 31/495C07D 209/12C07D 209/08C07D 215/00Y02A50/30
44
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Claims
Abstract
The present invention relates generally to the fields of bacteriology and mycology. More particularly, the present invention provides novel inhibitors of multidrug transport proteins that may be used in combination with existing antibacterial agent and/or antifungal agents to increase the toxic effects of the antimicrobial agents. More specifically, the present invention provides methods and compositions for enhancing the antibacterial action of fluoroquinolones by administering fluoroquinolones in combination with an inhibitor of multidrug transporters and of enhancing the antifungal action of azole antifungal agents by administering an azole antifungal agent in combination with an inhibitor of multidrug transporters. Compositions comprising indole, urea, quinoline or aromatic amide based inhibitors also are disclosed.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for enhancing the antibacterial action of fluoroquinolones comprising contacting a bacterium with an inhibitor of NorA, wherein said inhibitor is an indole, a urea, an aromatic amide or a quinoline.
2 . The method of claim 1 , wherein said inhibitor is an indole.
3 . The method of claim 1 , wherein said inhibitor is a urea.
4 . The method of claim 1 , wherein said inhibitor is an aromatic amide.
5 . The method of claim 1 , wherein said inhibitor is a quinoline.
6 . The method of claim 2 , wherein said indole has the general formula:
wherein R 1 is phenyl, 2-naphthyl, o-anisole, R 2 is H or CH 3 , R 1 and R 2 are two naphthyl groups fused to the indole ring, R 3 is H, R 4 is NO 2 , SO 3 H, NH 2 and CF 3 or CCl 3 , R 5 is H, and R 6 is H.
7 . The method of claim 6 , wherein R 1 is phenyl and R 4 is SO 3 H or NO 2 .
8 . The method of claim 6 , wherein R 1 is 2-naphthyl and R 4 is CCl 3 or CF 3 .
9 . The method of claim 6 , wherein R 1 is o-anisole and R 4 is NO 2 .
10 . The method of claim 6 , wherein R 1 and R 2 are two naphthyl groups fused to the indole ring.
11 . The method of claim 6 , wherein R 1 is phenyl and R 2 is CH 3 .
12 . The method of claim 3 , wherein said urea has the general formula:
wherein R 1 is OR, Br, Cl, or F, R 2 is OR, NHCO 2 R, Cl, F, or H, R 3 is Cl, Br, OR, or CO 2 R, R 4 is Cl or Br, R 5 is H, R 6 is H, R 7 is H, R 8 is a conjugated or aromatic system, R 9 is H, OR, Cl or Br, R 10 is H, OR, or Cl.
13 . The method of claim 12 , wherein R 3 is Cl or CO 2 R and R 6 is Cl or CO 2 R.
14 . The method of claim 12 , wherein R 1 is OR, F, Cl, CO 2 R and R 6 is Cl or F.
15 . The method of claim 4 , wherein said aromatic amide has the general formula:
wherein R 1 , R 4 and R 5 are H, R 2 and/or R 3 are small electron-withdrawing groups, and R 6 is substituted or unsubstituted alkyl of at least six atoms including O, N or S, with or without a phenyl ring.
16 . The method of claim 15 , wherein said electron-withdrawing group is selected from the group consisting of Cl, F and Br.
17 . The method of claim 15 , wherein R 4 and R 6 are smaller conjugated systems of 2-6 atoms of C, O, N or S, and includes a phenyl ring.
18 . The method of claim 5 , wherein said quinoline has the general formula:
wherein R 2 is 3,4-dimethoxybenzene, R 3 is H, R 4 is CO 2 R, C(═O)NHR, or NHC(═O)R, R 5 is H, R 6 is H, NO 2 , SO 3 H, NH 2 , CF 3 or CCl 3 , R 7 is an alkyl group, NO 2 , SO 3 H, NH 2 , CF 3 or CCl 3 and R 8 is H.
19 . The quinoline of claim 18 , wherein R 2 is p-toluene, R 4 is CO 2 NH 2 and R 6 is F or Cl.
20 . The quinoline of claim 18 , wherein R 2 is NR 2 and R 8 is OR or NC(═O)R.
21 . The method of claim 1 , wherein said bacterium is Streptococcus pneumonia, Enterococcus faecalis, Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermis, Mycobacterium smegmatis and Serratia marcesens.
22 . An indole having the general formula:
wherein R 1 is phenyl, 2-naphthyl, o-anisole, R 2 is H or CH 3 , R 1 and R 2 are two naphthyl groups fused to the indole ring, R 3 is H, R 4 is NO 2 , SO 3 H, NH 2 and CF 3 or CCl 3 , R 5 is H, and R 6 is H.
23 . The indole of claim 22 , wherein R 1 is phenyl and R 4 is SO 3 H or NO 2 .
24 . The indole of claim 22 , wherein R 1 is 2-naphthyl and R 4 is CCl 3 or CF 3 .
25 . The indole of claim 22 , wherein R 1 is o-anisole and R 4 is NO 2 .
26 . The indole of claim 22 , wherein R 1 and R 2 are two naphthyl groups fused to the indole ring.
27 . The indole of claim 22 , wherein R 1 is phenyl and R 2 is CH 3 .
28 . A urea having the general formula:
wherein R 1 is OR, Br, Cl, or F, R 2 is OR, NHCO 2 R, Cl, F, or H, R 3 is Cl, Br, OR, or CO 2 R, R 4 is Cl or Br, R 5 is H, R 6 is H, R 7 is H, R 8 is a conjugated or aromatic system, R 9 is H, OR, Cl or Br, R 10 is H, OR, or Cl.
29 . The urea of claim 28 , wherein R 3 is Cl or CO 2 R and R 6 is Cl or CO 2 R.
30 . The urea of claim 28 , wherein R 1 is OR, F, Cl, CO 2 R and R 6 is Cl or F.
31 . An aromatic amide having the general formula:
wherein R 1 , R 4 and R 5 are H; R 2 and/or R 3 are small electron withdrawing groups, and R 6 is substituted or unsubstituted alkyl of at least six atoms including C, O, N or S, with or without a phenyl ring.
32 . The aromatic amide of claim 31 , wherein R 4 and R 6 are smaller conjugated systems of 2-6 atoms of C, O, N or S, and includes a phenyl ring.
33 . A quinoline having the general formula:
wherein R 2 is 3,4-dimethoxybenzene, R 3 is H, R 4 is CO 2 R, C(═O)NHR, or NHC(═O)R, R 5 is H, R 6 is H, NO 2 , SO 3 H, NH 2 , CF 3 or CCl 3 , R 7 is an alkyl group, NO 2 , SO 3 H, NH 2 , CF 3 or CCl 3 and R 8 is H.
34 . The quinoline of claim 33 , wherein R 2 is p-toluene, R 4 is CO 2 NH 2 and R 6 is F or Cl.
35 . The quinoline of claim 33 , wherein R 2 is NR 2 and R 8 is OR or NC(═O)R.
36 . A method of screening for inhibitors of NorA comprising:
(a) providing a cell expressing only a single functional transporter, said transporter being Nor A; (b) contacting said cell with a transportable element in the presence of a candidate inhibitor substance; and (c) comparing the transport of said element by said cell with the transport of said element in the absence of said candidate inhibitor substance.
37 . The method of claim 36 , wherein said cell is a bacterial cell.
38 . The method of claim 37 , wherein said bacterial cell is a Gram negative bacterial cell.
39 . The method of claim 37 , wherein said bacterial cell is a Gram positive bacterial cell.
40 . The method of claim 39 , wherein said Gram positive bacterial cell is a Bacillus subtilis cell.
41 . The method of claim 40 , wherein said B. subtilis cell contains disrupted Bmr and Blt genes.
42 . The method of claim 36 , wherein said NorA is Staphylococcus aureus NorA, Streptococcus pneumoniae multidrug transporter, or Enterococcus faecalis multidrug transporter.
43 . The method of claim 36 , wherein said transportable element is ethidium bromide.
44 . The method of claim 36 , wherein said transportable element is a fluoroquinolone.
45 . A method for treating a subject with a bacterial infection comprising providing to said subject a fluoroquinolone and an inhibitor of NorA, wherein said inhibitor is an indole, a urea or an aromatic amide.
46 . The method of claim 45 , wherein said bacterium is Streptococcus pneumonia, Enterococcus faecalis, Staphylococcus aureus, Neisseria gonorrhea, Mycobacterium tuberculosis, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermis, Mycobacterium smegmatis and Serratia marcesens
47 . A pharmaceutical composition comprising a fluoroquinolone and an inhibitor of NorA, wherein said inhibitor is an indole, a urea or an aromatic amide.
48 . The composition of claim 43 , wherein said fluoroquinolone is selected from the group consisting of Sparfloxacin, Ciprofloxacin, Moxifloxacin, Levofloxacin, Grepafloxacin, Temafloxacin, Clinafloxacin, Bay 12-8039, Trovafloxacin, DU6859a and Sarafloxacin.
49 . A method of enhancing the antifungal action of azole antifungal agents comprising contacting a fungus with an inhibitor of a fungal multidrug transport protein, wherein said inhibitor is an indole, a urea or an aromatic amide.
50 . The method of claim 49 , wherein said indole has the general formula I.
51 . The method of claim 49 , wherein said urea has the general formula II.
52 . The method of claim 49 , wherein said aromatic amide has the general formula III.
53 . The method of claim 49 , wherein said fungus is from a species selected from the group consisting of Candida, Cryptococcus, Blastomyces, Histoplasma, Torulopis, Coccidioides, Paracoccidioides and Aspergillis.
54 . A method of screening for inhibitors of a fungal multidrug transporter comprising:
(a) providing a cell expressing only a single functional transporter, said transporter being fungal multidrug transporter; (b) contacting said cell with a transportable element in the presence of a candidate inhibitor substance; and (c) comparing the transport of said element by said cell with the transport of said element in the absence of said candidate inhibitor substance.
55 . The method of claim 54 , wherein said cell is a fungal cell.
56 . The method of claim 55 , wherein said fungal cell is selected from a species selected from the group consisting of Candida, Cryptococcus, Blastomyces, Histoplasma, Torulopis, Coccidioides, Paracoccidioides and Aspergillis.
57 . The method of claim 56 , wherein said cell is from the Candida species.
58 . The method of claim 54 , wherein said multidrug transporter is a Candida multidrug transporter.
59 . The method of claim 54 , wherein said antifungal agent is a triazole antifungal agent.
60 . The method of claim 54 , wherein said triazole is selected from the group consisting of ketoconazole, miconazole, itraconazole, fluconazole, griseofluconazole, clotrimazole, econazole, terconazole and butaconazole.
61 . A method of treating a subject with a fungal infection comprising providing to said subject an azole antifungal agent and an inhibitor of a fungal multidrug transport protein, wherein said inhibitor is an indole, a urea, or an aromatic amide.
62 . The method of claim 61 , wherein said fungal infection is mediated by a fungus of a species selected from the group consisting of Candida, Cryptococcus, Blastomyces, Histoplasma, Torulopis, Coccidioides, Paracoccidioides and Aspergillis.
62 . The method of claim 61 wherein said antifungal agent is selected from the group consisting of ketoconazole, miconazole, itraconazole, fluconazole, griseofluconazole, clotrimazole, econazole, terconazole and butaconazole.
63 . A pharmaceutical composition comprising an azole antifungal agent and an inhibitor of a fungal multidrug transporter, wherein said inhibitor is an indole, a urea, or an aromatic amide.
64 . The pharmaceutical composition of claim 63 , wherein said antifungal agent is an azole selected from the group consisting of ketoconazole, miconazole, itraconazole, fluconazole, griseofluconazole, clotrimazole, econazole, terconazole and butaconazole.
65 . A method for suppressing the emergence of fluoroquinolone resistance in bacteria, comprising contacting a bacterium with an efflux inhibitor, wherein said inhibitor is an indole, a urea, an aromatic amide or a quinoline.Cited by (0)
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