Analogs of indole-3-carbinol and their use as agents against infection
Compounds useful as antibacterial agents are provided. The compounds are analogs of indole-3-carbinol and have a backbone selected from dihydroindolo[2,3-b]carbazole, 2,2′-diindolylmethane, 2′,3-diindolylmethane, and 3,3′-diindolylmethane. The compounds are useful therapeutic and prophylactic treatment of bacterial infections in mammals. Methods of synthesis of the compounds are provided, as are pharmaceutical compositions containing the compounds.
1. A compound having the structure of formula (I)
wherein:
R 1 , R 4 , R 5 , and R 8 are hydrogen;
R 2 , R 3 , R 6 , R 7 , and R 9 are substituents independently selected from the group consisting of hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 5 -C 20 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, C 2 -C 24 alkylcarbonyl, C 6 -C 20 arylcarbonyl, halocarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C 1 -C 24 alkyl)-substituted carbamoyl, di-(C 1 -C 24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, dihydroxyboryl, di-(C 1 -C 24 )-alkoxyboryl, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C 1 -C 24 alkyl)-substituted amino, mono- and di-(C 5 -C 20 aryl)-substituted amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof;
R 11 and R 12 are independently selected from the group consisting of hydrogen, formyl, C 1 -C 24 alkyl, C 6 -C 24 aralkyl, C 2 -C 24 alkoxycarbonyl, amino-substituted C 1 -C 24 alkyl, (C 1 -C 24 alkylamino)-substituted C 1 -C 24 alkyl, di-(C 1 -C 24 alkyl)amino-substituted C 1 -C 24 alkyl, and nitrogen protecting groups; and
R 10 is —O-L-N(R y1 )(R y2 )(R y3 ) n2 , —O-L-SR z1 , or has the structure
wherein:
L is a linker selected from a C 1 -C 12 straight chain, C 2 -C 12 branched, or C 3 -C 12 cyclic alkylene group that may be substituted, unsubstituted, heteroatom containing, or a combination thereof, and an alkylene oxide oligomer;
L 1 is a linker selected from a bond, a C 1 -C 12 straight chain, C 2 -C 12 branched, or C 3 -C 12 cyclic alkylene group that may be substituted, unsubstituted, heteroatom containing, or a combination thereof, and an alkylene oxide oligomer;
R y1 and R y2 are independently selected from hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 5 -C 20 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, amino, imino, C 1 -C 24 alkylsulfonyl, and C 5 -C 20 arylsulfonyl, any of which may be further substituted and/or heteroatom-containing where such groups permit, or wherein R y1 and R y2 are taken together to form a cyclic or polycyclic group that may be unsubstituted, substituted, and/or further heteroatom-containing;
R y3 is selected from hydrogen and C 1 -C 12 alkyl;
n2 is selected from 0 and 1;
R z1 is selected from C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 5 -C 20 aryl, C 6 -C 24 alkaryl, and C 6 -C 24 aralkyl, any of which may be further substituted and/or heteroatom-containing where such groups permit;
Q 1 and Q 2 are selected from a bond and —CH 2 —;
Q 3 is selected from a bond, —CH(R a3 )—, —O—, and —NR a4 —, provided that Q 3 is not a bond when both Q 1 and Q 2 are bonds;
R a1 and R a2 are independently selected from hydrogen, hydroxyl, amino, C 1 -C 12 alkyl-substituted amino, and C 1 -C 12 alkyl;
R a3 and R a4 are independently selected from hydrogen, C 1 -C 12 alkyl, unsubstituted amino, and mono- or di-(C 1 -C 12 alkyl)-substituted amino;
Q 4 , Q 5 , and Q 6 are selected from —CHR b1 — and —NR b1 —, where R b1 is selected from hydrogen, hydroxyl, amino, C 1 -C 12 alkyl-substituted amino, and C 1 -C 12 alkyl;
p1 is an integer in the range of 0-2;
Q 7 is selected from —CH< and —N<;
Q 8 , Q 9 , Q 10 , and Q 11 are independently selected from —CH(R e1 )—, ═C(R e1 )—, —NR e1 —, and —N═, where R e1 is selected from hydrogen, hydroxyl, amino, C 1 -C 12 alkyl-substituted amino, and C 1 -C 12 alkyl, provided that: (1) any two of Q 8 , Q 9 , Q 10 , and Q 11 that are adjacent each other may be linked by a double bond, with the proviso that no more than two double bonds are present, and, when two double bonds are present, a single bond is present between them; and (2) any two adjacent R e1 groups may be taken together to form a 5- or 6-membered ring that may be further substituted and may have one or more heteroatoms; and
R c1 , R c2 , and R c3 are independently selected from hydrogen, C 1 -C 24 alkyl, and C 5 -C 20 aryl, any of which may be further substituted and/or heteroatom-containing, or wherein any two of R c1 , R c2 , and R c3 may be taken together to form a cyclic or polycyclic group that may be unsubstituted, substituted, and/or further heteroatom-containing, or
a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein:
n2 is 1;
R y1 , R y2 , and R y3 are independently selected from hydrogen and C 1 -C 12 alkyl; and
R z1 is selected from C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 5 -C 20 aryl, C 6 -C 24 alkaryl, and C 6 -C 24 aralkyl.
3. The compound of claim 1 , wherein:
n2 is 1;
R y1 , R y2 , and R y3 are independently selected from hydrogen and C 1 -C 12 alkyl;
R z1 is selected from C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 5 -C 20 aryl, C 6 -C 24 alkaryl, and C 6 -C 24 aralkyl; and
R 10 is —O-L-N(R y1 )(R y2 )(R y3 ), or —O-L-SR z1 .
4. The compound of claim 1 , wherein:
n2 is 1;
R y1 , R y2 , and R y3 are independently selected from hydrogen and C 1 -C 12 alkyl;
R z1 is selected from C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 5 -C 20 aryl, C 6 -C 24 alkaryl, and C 6 -C 24 aralkyl; and
R 10 has the structure
5. The compound of claim 1 , wherein L is —(CH 2 ) m —, where m is an integer from 1 to 6.
6. The compound of claim 1 , wherein R 2 and R 6 are independently selected from hydrogen, halo, formyl, cyano, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 1 -C 24 , C 5 -C 20 aryloxy, carbamoyl, C 2 -C 24 alkoxycarbonyl, and amino.
7. The compound of claim 1 , R 9 is selected from hydrogen, halo, cyano, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, and amino.
8. The compound of claim 7 , wherein:
L is a C 1 -C 12 straight chain alkylene group or an alkylene oxide oligomer; and
L1 is selected from a bond, a C1-C12 straight chain alkylene group, and an alkylene oxide oligomer.
9. The compound of claim 7 , wherein:
Q 1 and Q 2 are —CH 2 —; and
Q 3 is selected from —CH(R a3 )—, —O—, and —NR a4 —.
10. The compound of claim 7 , wherein Q 4 and Q 5 , are selected —CHR b1 —.
11. The compound of claim 7 , wherein: Q 8 , Q 9 , Q 10 , and Q 11 are independently selected from ═C(R e1 )— and —N═.
12. The compound of claim 1 , wherein R 3 and R 7 are hydrogen.
13. The compound of claim 1 , wherein R 3 , R 7 , R 11 and R 12 are hydrogen.
14. The compound of claim 1 , wherein R 3 , R 7 , R 9 , R 11 and R 12 are hydrogen.
15. The compound of claim 1 wherein R 10 is an alkoxy group substituted with a nitrogen containing heterocyclic ring.
16. The compound of claim 12 wherein R 10 is an alkoxy group substituted with a nitrogen containing heterocyclic ring.
17. The compound of claim 13 wherein R 10 is an alkoxy group substituted with a nitrogen containing heterocyclic ring.
18. The compound of claim 14 wherein R 10 is an alkoxy group substituted with a nitrogen containing heterocyclic ring.
19. The compound of claim 1 , wherein R 2 and R 6 are halo and R 10 is an alkoxy group substituted with a nitrogen containing heterocyclic ring.
20. The compound of claim 12 , wherein R 2 and R 6 are halo and R 10 is an alkoxy group substituted with a nitrogen containing heterocyclic ring.
21. The compound of claim 13 , wherein R 2 and R 6 are halo and R 10 is an alkoxy group substituted with a nitrogen containing heterocyclic ring.
22. The compound of claim 14 , wherein R 2 and R 6 are halo and R 10 is an alkoxy group substituted with a nitrogen containing heterocyclic ring.
23. A formulation comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
24. A method for treating a bacterial infection in a mammalian individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of claim 1 .
25. The method of claim 24 , wherein the bacteria are of the genus Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia, Chromobacterium, Brucella, Yersinia, Haemophilus, Bordetella , or Francisella.