Compositions of lipopeptide antibiotic derivatives and methods of use thereof
View Patent ↗The present invention provides derivatives of lipopeptide antibiotics that display antimicrobial activity against microorganisms, methods and compounds for synthesizing such antimicrobial derivatives and analogues, and methods of using the compounds in a variety of contexts, including in the treatment and prevention of microbial infections.
1. A compound and pharmaceutically acceptable salts thereof, according to structural formula (II):
R 1 is OH or NH 2 ;
L is selected from at least one amino acid, at least one substituted amino acid, and —O-PhC(═O)—;
R 2 is selected from —C(═O)R 5 , —C(═O)OR 5 , —C(═O)NHR 4 , —C(═O)NR 4 R 4 , —C(═S)NHR 4 , —C(═S)NR 4 R 4 , —C(═NR 4 )NHR 4 , and —C(═NR 4 )NR 4 R 4 ;
R 3 is at least one amino acid selected from Gly, β-alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, Lys, gDab, Sar, Orn, Dap, hLys, or any combination thereof;
R 4 is independently selected from (C 7 -C 10 ) alkyl, (C 17 -C 26 ) arylalkyl and 17 to 26 membered heteroarylalkyl, a branched or straight-chained, saturated or singly or multiply unsaturated aliphatic or hydroxy aliphatic moiety having a chain length of from 7 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, and at least one substituted amino acid; and
R 5 is independently selected from hydrogen, (C 1 -C 10 ) alkyl, (C 5 -C 10 ) aryl, 5 to 10 membered heteroaryl, (C 6 -C 26 ) arylalkyl and 6 to 26 membered heteroarylalkyl, a branched or straight chained, saturated or singly or multiply unsaturated aliphatic or hydroxy aliphatic moiety having a chain length of from 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid, and any combination thereof.
2. The compound of claim 1 wherein R 1 is OH.
3. The compound of claim 1 wherein R 1 is NH 2 .
4. The compound of claim 1 wherein R 2 is —C(═O)OR 5 or —C(═O)R 5 .
5. The compound of claim 1 wherein R 2 is —C(═O)R 5 .
6. The compound of claim 1 wherein R 2 is —C(═O)NHR 4 , —C(═S)NHR 4 , or —C(═NR 4 )NHR 4 .
7. The compound of claim 6 wherein R 2 is —C(═O)NHR 4 .
8. The compound of claim 1 wherein R 3 is at least one amino acid selected from glycine, β-alanine, sarcosine, lysine, or any combination thereof.
9. The compound of claim 8 wherein said at least one amino acid is two amino acids selected from glycine-lysine or sarcosine-lysine.
10. The compound of claim 8 wherein said at least one amino acid is glycine.
11. The compound of claim 8 wherein said at least one amino acid is β-alanine.
12. The compound of claim 5 wherein said compound is
13. The compound according to any one of claims 1 to 11 wherein L is at least one amino acid or at least one substituted amino acid selected from p-aminophenylacetyl, (p-aminophenylpropanoyl) n wherein n is 1 or 2, m-aminophenylacetyl, (m-aminophenylpropanoyl) n wherein n is 1 or 2, o-aminophenylacetyl, (o-aminophenylpropanoyl) n wherein n is 1 or 2, GABA, p-aminobenzoic acid (PABA), m-aminobenzoic acid, o-aminobenzoic acid, p-hydrazinobenzoic acid, m-hydrazinobenzoic acid, o-hydrazinobenzoic acid, p-amino-trans-cinnamyl, m-amino-trans-cinnamyl, o-amino-trans-cinnamyl, L-BBTA, or any combination thereof.
14. The compound of claim 4 wherein L is at least one amino acid selected from p-aminophenylacetyl, PABA, m-aminobenzoic acid, o-aminobenzoic acid, p-amino-trans-cinnamyl, m-amino-trans-cinnamyl, o-amino-trans-cinnamyl, or any combination thereof.
15. The compound of claim 14 wherein R 5 is a straight chain saturated aliphatic or hydroxy aliphatic moiety having a chain length of from 10 to 15 carbon atoms.
16. The compound of claim 14 or 15 wherein said compound is
17. A compound and pharmaceutically acceptable salts thereof, according to structural formula (IV):
R 1 is OH or NH 2 ;
L is independently selected from at least one amino acid, at least one substituted amino acid, —C(═O)—, —SO 2 , —C(═S)—, —P(═O)—, —OP(═O)—, —OC(═O)—, —NHC(═O)—, and —O-PhC(═O)—, with the proviso that L at Dab 9 is —C(═O)—;
R 2 is selected from —OR 4 , —SR 4 , NR 4 R 4 , —CN, —NO 2 , —N 3 , —C(═O)OR 4 , —C(═O)R 4 , —C(═O)NR 4 R 4 , —C(═S)NR 4 R 4 , —C(═NR 4 )NR 4 R 4 , —C(═O)H, —R 4 C(═O), —SO 2 R 4 , —S(═O)R 4 , —P(═O)(OR 4 ) 2 , —P(═O)(OR 4 ), —CO 2 H, —SO 3 H, —PO 3 H, halogen, trihalomethyl, (C 1 -C 25 )alkyl, substituted (C 1 -C 25 )alkyl, (C 1 -C 25 )heteroalkyl, substituted (C 1 -C 25 )heteroalkyl, (C 5 -C 10 )aryl, substituted (C 5 -C 10 )aryl, (C 5 -C 15 )arylaryl, substituted (C 5 -C 15 )arylaryl, (C 5 -C 15 )biaryl, substituted (C 5 -C 15 )biaryl, 5-10 membered heteroaryl, substituted 5 to 10 membered heteroaryl, (C 6 -C 26 )arylalkyl, substituted (C 6 -C 26 )arylalkyl, 6 to 26 membered heteroarylalkyl, substituted 6 to 26 membered heteroarylalkyl, at least one amino acid, and at least one substituted amino acid;
R 3 is at least one amino acid or substituted amino acid selected from Gly, β-alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, Lys, gDab, Sar, Orn, Dap, and hLys; and
R 4 is independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 5 -C 10 )aryl, 5 to 10 membered heteroaryl, (C 6 -C 26 )arylalkyl and 6 to 26 membered heteroarylalkyl, a branched or straight-chained, saturated or singly or multiply unsaturated aliphatic or hydroxy aliphatic moiety having a chain length of from 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid, and any combination thereof.
18. The compound of claim 17 wherein R 1 is OH.
19. The compound of claim 17 wherein R 1 is NH 2 .
20. The compound of claim 17 wherein at least one of L and R 3 further comprise at least one protecting group.
21. A compound and pharmaceutically acceptable salts thereof, wherein the compound is
22. A compound and pharmaceutically acceptable salts thereof, wherein the compound is
23. A pharmaceutical composition, comprising a compound according to claim 1 or 17 and a pharmaceutically acceptable carrier, excipient, or diluent.
24. A method for treating a bacterial infection, comprising administering to a subject in need thereof a compound according to claim 1 or 17 .
25. A method for treating a bacterial infection, comprising administering to a subject in need thereof a pharmaceutical composition according to claim 23 .
26. The method of claim 25 wherein the bacterial infection is caused by a Gram-positive microorganism.
27. The method according to claim 26 wherein the Gram-positive microorganism is selected from a Streptococcus , a Staphylococcus , an Enterococcus , a Bacillus , a Corynebacterium , a diphtheroid, and a Listeria.
28. The method according to claim 26 wherein the Gram-positive microorganism is Streptococcus pyogenes, Streptococcus pneumoniae , or Viridans Streptococcus.
29. The method according to claim 26 wherein the Gram-positive microorganism is Staphylococcus aureus, Staphylococcus epidermidis , or coagulase-negative Staphylococcus.
30. The method according to claim 26 wherein the Gram-positive microorganism is Enterococcus faecalis or Enterococcus faecium.
31. The method according to claim 26 wherein the Gram-positive microorganism is drug resistant.
32. The method according to claim 31 wherein the drug resistant microorganism is penicillin-resistant Streptococcus pneumoniae , penicillin-intermediate Streptococcus pneumoniae , or a multidrug-resistant Streptococcus.
33. The method according to claim 31 wherein the drug resistant microorganism is methicillin-resistant Staphylococcus aureus , methicillin-resistant Staphylococcus epidermidis , vancomycin-intermediate Staphylococcus aureus , or a multidrug-resistant Staphylococcus.
34. The method according to claim 31 wherein the drug resistant microorganism is vancomycin-resistant Enterococcus or multidrug resistant Enterococcus.
35. The method according to claim 25 wherein the bacterial infection is selected from a complicated or uncomplicated skin infection; a surgical wound infection; an intra-abdominal infection; a urinary tract infection; pyelonephritis; a nosocomial infection; a nosocomial pneumonia; a community-acquired infection; a community-acquired pneumonia; and infective endocarditis.
36. The method according to claim 35 wherein the complicated or uncomplicated skin infection is impetigo, folliculitis, furunculosis, eethyma, erysipelas, cellulitis, acute paronychia, felon, necrotizing fasciitis, Staphylococcal scalded skin infection, nodular lymphangitis, preseptal cellulitis, or periorbital cellulitis.
37. The method according to claim 35 wherein the nosocomial infection is caused by a Staphylococcus or an Enterococcus.
38. The method according to claim 37 wherein the Staphylococcus is S. aurueus or methicillin-resistant S. aureus.
39. The method according to claim 37 wherein the Enterococcus is vancomycin-resistant Enterococcus.
40. The method according to claim 35 wherein the community-acquired pneumonia is caused by Streptococcus pneumoniae.
41. The method according to claim 35 wherein the urinary tract infection or pyelonephritis is caused by an Enterococcus.
42. A method for treating a bacterial infection, comprising administering to a subject in need thereof a pharmaceutical composition comprising an antibacterial compound, wherein the antibacterial compound is
43. The method according to claim 42 wherein the compound is
44. The method according to claim 42 wherein the compound is
45. The method according to claim 42 wherein the compound is
46. The method according to claim 42 wherein the compound is
47. The method according to claim 42 wherein the compound is
48. A compound and pharmaceutically acceptable salts thereof, wherein the compound is
49. The method according to claim 42 , wherein the compound is