阅读说明：本技术 肽类抗生素 (Peptide antibiotics ) 是由 M·库伯 M·布拉斯科维奇 A·加拉尔多戈多伊 K·汉斯福德 A·埃利奥特 B·贝克尔 于 2018-11-02 设计创作，主要内容包括：提供了一系列新型化合物。这些新型化合物可以表现出广谱抗菌和抗真菌活性。这些化合物对新出现的多黏菌素耐药性细菌具有活性。当与其它药物活性剂联用时,这些化合物也可以有效。(A series of novel compounds are provided. These novel compounds may exhibit broad spectrum antibacterial and antifungal activity. These compounds are active against emerging polymyxin-resistant bacteria. These compounds may also be effective when used in combination with other pharmaceutically active agents.)

1. A compound of formula (I) or a salt or stereoisomer thereof:

wherein

Y₁、Y₂、Y₃、Y₄、Y₅、Y₆、Y₇And Y₈Independently selected from C and N;

R₁、R₃、R₄、R₅、R₆、R₇and R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

R₁’、R₂’、R₃’、R₄’、R₅’、R₆’、R₇’、R₈' and R₉' is independently selected from hydrogen and substituted or unsubstituted alkyl, or R₁' and R₁、R₃' and R₃、R₄' and R₄、R₅' and R₅、R₆' and R₆、R₇' and R₇And R₈' and R₈Each pair of (a) may together form a cycloalkyl group;

n is an integer of 0, 1,2 or 3; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted, wherein Z does not contain more than one (1) peptide or valence bond;

wherein when R is₄Is composed ofR₅Is composed ofR₈Is composed ofWhen Z is not selected fromWhen R is₄Is composed ofR₅Is composed ofR₈Is composed ofWhen Z is not selected from When R is₄Is composed ofR₅Is composed ofR₈Is composed ofWhen Z is not selected fromWhen R is₄Is composed ofR₅Is composed ofR₈Is composed ofWhen Z is not selected from When R is₁Is composed ofR₄Is composed ofR₅Is composed ofR₈Is composed ofWhen Z is not selected fromAnd when R is₄Is composed ofR₅Is composed ofR₈Is composed ofWhen Z is not selected from

2. The compound of claim 1, wherein the compound is of formula (Ia):

wherein

Y₁、Y₂、Y₃、Y₄、Y₅、Y₆、Y₇And Y₈Independently selected from C and N;

R₁、R₃、R₄、R₅、R₆、R₇and R₈Independently selected from hydrogen, alkyl, alkeneA group, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

n is an integer of 0, 1,2 or 3; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

3. The compound of claim 2, wherein the compound is of formula (Ib):

wherein

Y₁And Y₂Independently selected from C and N;

R₁、R₃、R₄、R₅、R₆、R₇and R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

n is an integer of 0, 1,2 or 3; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

4. The compound of claim 3, wherein the compound is of formula (Ic):

wherein

R₄、R₅、R₆、R₇And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

5. The compound of claim 4, wherein the compound is of formula (Id):

wherein

R₆、R₇And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

6. the compound of claim 3, wherein the compound is of formula (Ie):

wherein

R₁、R₃、R₄、R₅、R₆、R₇And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

R₁’、R₂’、R₃’、R₄’、R₅’、R₆’、R₇’、R₈' and R₉' is independently selected from hydrogen and substituted or unsubstituted alkyl or wherein R is₁' and R₁、R₃' and R₃、R₄' and R₄、R₅' and R₅、R₆' and R₆、R₇' and R₇And R₈' and R₈Each pair of (a) or (b) together may form a cycloalkyl group; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

7. The compound of claim 3, wherein the compound is of formula (If):

wherein

R₁And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

8. The compound of claim 3, wherein the compound is of formula (Ig):

wherein

R₄、R₅And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

9. The compound of any one of claims 1-3, 6 and 7, wherein R₁Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 amine, C1-C4 amide, aryl and heteroaryl, each of which may be substituted or unsubstituted.

10. The compound of claim 9, wherein R₁Selected from the group consisting of:

11. the compound of any one of claims 1-3 and 6, wherein R₃Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 amine, C1-C6 amide, aryl and heteroaryl, each of which may be substitutedSubstituted or unsubstituted.

12. The compound of claim 11, wherein R₃Selected from the group consisting of:

13. the compound of any one of claims 1-4, 6 and 8, wherein R₄Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 amine, C1-C6 amide, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which may be substituted or unsubstituted.

14. The compound of claim 13, wherein R₄Is selected from

15. The compound of any one of claims 1-4, 6 and 8, wherein R₅Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 amine, C1-C6 amide, C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which may be substituted or unsubstituted.

16. The compound of claim 15, wherein R₅Selected from the group consisting of:

17. the compound according to any one of claims 1 to 6,wherein R is₆Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 amine, C1-C6 amide, aryl, heteroaryl, and heterocyclic, each or said groups may be substituted or unsubstituted.

18. The compound of claim 17, wherein R₆Selected from the group consisting of:

19. the compound of any one of claims 1-6, wherein R₇Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 amine, C1-C6 amide, C3-C10 cycloalkyl, aryl and heteroaryl, each or said groups may be substituted or unsubstituted.

20. The compound of claim 19, wherein R₇Selected from the group consisting of:

21. the compound of any one of claims 1-8, wherein R₈Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 amine, C1-C6 amide, aryl and heteroaryl, each or said groups may be substituted or unsubstituted.

22. The compound of claim 21, wherein R₈Selected from the group consisting of:

23. a compound according to any one of claims 1 to 22Wherein Z isWherein R is₁₀Selected from the group consisting of C1-C18 alkyl, C2-C18 alkenyl, C1-C6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

24. The compound of claim 23, wherein R₁₀Is a substituted or unsubstituted C1-C13 alkyl group.

25. A pharmaceutical composition comprising a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.

26. The pharmaceutical composition of claim 25, further comprising at least one additional pharmaceutically active agent.

27. The pharmaceutical composition of claim 26, wherein the at least one other pharmaceutically active agent is selected from the group consisting of antibiotic agents, antiviral agents, agents that disrupt biofilms, anti-inflammatory agents, agents known to enhance the efficacy of antibiotics, and antifungal agents.

28. The pharmaceutical composition of claim 27, wherein the at least one other pharmaceutically active agent is selected from rifampicin and minocycline.

29. The pharmaceutical composition of claim 27 or 28, wherein the at least one other pharmaceutically active agent is selected from rifampin (rifampin), minocycline, clarithromycin, azithromycin, fusidic acid, mupirocin, retastatin, meropenem, aztreonam, clarithromycin, erythromycin, novobiocin, telithromycin, polymyxin E, polymyxin B, fosfomycin, ciprofloxacin, tetracycline, gentamicin, vancomycin, quinupristin-dalfopristin, ramoplanin, teicoplanin, levofloxacin, arenicin-3, linezolid, and anti-biologic peptides.

30. A method of treating or preventing a disease, disorder or condition in a subject, comprising the step of administering to the subject an effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition of any one of claims 24-29, thereby treating or preventing the disease, disorder or condition.

31. The method of claim 30, wherein the disease, disorder or condition is associated with a bacterial or fungal infection.

32. Use of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of any one of claims 8-10, in the manufacture of a medicament for treating a disease, disorder, or condition.

33. The use of claim 32, wherein the disease, disorder or condition is associated with a bacterial or fungal infection.

Technical Field

The present invention relates to the field of medical treatment. More particularly, the present invention relates to antimicrobial compounds and uses thereof. Most particularly, the present invention relates to novel peptide antimicrobial agents for use in the treatment of bacterial or fungal infections.

Background

Any reference in this specification to background art is not to be construed as an admission that the art forms part of the common general knowledge in australia or elsewhere.

The emergence of multidrug resistant bacteria and fungi represents a serious and increasing threat to human life. Bacterial sepsis causes millions of deaths each year, and multidrug-resistant bacteria are responsible for a large number of these deaths. Sepsis is most commonly caused by gram-positive staphylococcus aureus (staphylococcus aureus) and Streptococcus pyogenes (Streptococcus pyogenes) and gram-negative Klebsiella species (Klebsiella spp.), Escherichia coli (Escherichia coli) and Pseudomonas aeruginosa (Pseudomonas aeruginosa). Unfortunately, highly multidrug resistant gram-negative bacteria have been increasing unreliably. The emergence of multidrug resistant gram-negative bacteria has led to a return to the clinical use of "last resort" antibiotics such as polymyxin B and polymyxin E (polymyxin E). However, the emergency situation of polymyxin-resistant bacteria is a worrying problem because there is currently no adequate treatment for these strains.

One of the limitations to the widespread use of polymyxins is their nephrotoxicity. This complicates treatment and may result in treatment being delivered at sub-optimal doses and/or treatment being terminated. Octapeptoids have somewhat similar structures to polymyxin. However, octapeptoids have not been extensively studied as antibiotics against polymyxin resistant bacteria.

There are few effective treatments for fungal infections and resistance to antibiotics used to treat fungal infections is increasing. Naturally occurring octapeptycins have been demonstrated to be active against fungi, but have not been extensively studied. It would be further advantageous if these novel antimicrobial agents could exhibit enhanced efficacy against fungi and/or reduced nephrotoxicity in human and veterinary animals.

It is clear that there is a need to develop new antibiotics that are effective against infectious microorganisms, in particular against polymyxin resistant bacteria. It would be further advantageous if these new antibiotics could exhibit one or more of reduced nephrotoxicity, improved stability, and increased efficacy. Alternatively, it is desirable to have a larger selection of antibiotics that can be selected to address a particular patient's infection.

Summary of The Invention

In a first aspect, although not necessarily the only or indeed the broadest aspect, the invention resides in a compound of formula (I):

wherein

Y₁、Y₂、Y₃、Y₄、Y₅、Y₆、Y₇And Y₈Independently selected from C and N;

R₁、R₃、R₄、R₅、R₆、R₇and R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

R₁’、R₂’、R₃’、R₄’、R₅’、R₆’、R₇’、R₈' and R₉' is independently selected from hydrogen and substituted or unsubstituted alkyl, or R₁' and R₁、R₃' and R₃、R₄' and R₄、R₅' and R₅、R₆' and R₆、R₇' and R₇And R₈' and R₈Each pair of (a) may together form a cycloalkyl group;

n is an integer of 0, 1,2 or 3; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

In one embodiment, the compound of formula (I) may be selected from compounds of formula (Ia) or salts or stereoisomers thereof:

wherein

Y₁、Y₂、Y₃、Y₄、Y₅、Y₆、Y₇And Y₈Independently selected from C and N;

R₁、R₃、R₄、R₅、R₆、R₇and R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

n is an integer of 0, 1,2 or 3; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

In one embodiment, the compound of formula (I) or (Ia) may be selected from compounds of formula (Ib) or salts or stereoisomers thereof:

wherein

Y₁And Y₂Independently selected from C and N;

R₁、R₃、R₄、R₅、R₆、R₇and R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

n is an integer of 0, 1,2 or 3; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

In a preferred embodiment, the compound of formula (I), (Ia) or (Ib) may be selected from compounds of formula (Ic) or salts or stereoisomers thereof:

wherein

R₄、R₅、R₆、R₇And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

In another preferred embodiment, the compound of formula (I), (Ia), (Ib) or (Ic) may be selected from compounds of formula (Id) or salts or stereoisomers thereof:

wherein

R₆、R₇And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

in another embodiment, the compound of formula (I) may be selected from compounds of formula (Ie) or salts or stereoisomers thereof:

wherein

R₁、R₃、R₄、R₅、R₆、R₇And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted;

R₁’、R₂’、R₃’、R₄’、R₅’、R₆’、R₇’、R₈' and R₉' is independently selected from hydrogen and substituted or unsubstituted alkyl or wherein R is₁' and R₁、R₃' and R₃、R₄' and R₄、R₅' and R₅、R₆' and R₆、R₇' and R₇And R₈' and R₈Each or may together form a cycloalkyl group; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

In one embodiment, the compound of formula (I), (Ia), (Ib), (Ic) or (Id) may be selected from compounds of formula (If) or salts or stereoisomers thereof

Wherein

R₁And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

In one embodiment, the compound of formula (I), (Ia), (Ib) or (Ic) may be selected from compounds of formula (Ig) or salts or stereoisomers thereof:

wherein

R₄、R₅And R₈Independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted; and is

Z is selected fromWherein

R₁₀Selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, each of which may be substituted or unsubstituted.

In a second aspect, the invention resides in a pharmaceutical composition comprising a compound of the first aspect or a pharmaceutically acceptable salt, solvate, prodrug thereof and a pharmaceutically acceptable carrier, diluent and/or excipient.

In one embodiment, the pharmaceutical composition further comprises a therapeutic agent. The therapeutic agent is selected from the group consisting of antibiotic agents, antifungal agents, antiviral agents, biofilm disrupters, anti-inflammatory agents, and agents known to enhance the efficacy of antibiotics.

In a third aspect, the invention resides in a method of treating or preventing a disease, disorder or condition in a subject, comprising the steps of: administering to the subject an effective amount of a compound of the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition of the second aspect, thereby treating or preventing the disease, disorder or condition.

Suitably, the disease, disorder or condition is associated with a bacterial or fungal infection.

In one embodiment, the compound of the first aspect further comprises the step of administering a therapeutic agent. The therapeutic agent is selected from the group consisting of antibiotic agents, antifungal agents, antiviral agents, biofilm disrupters, anti-inflammatory agents, and agents known to enhance the efficacy of antibiotics. In one embodiment, the therapeutic agent is co-administered with, administered before, or administered after the compound of the first aspect.

In a fourth aspect, the invention resides in the use of a compound of the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof or a pharmaceutical composition of the second aspect in the manufacture of a medicament for the treatment of a disease, disorder or condition.

In another aspect, the invention resides in a compound of the first aspect for use in the treatment of a disease, disorder or condition.

Suitably, the disease, disorder or condition is associated with a bacterial or fungal infection.

Where appropriate, various features and embodiments of the invention described in the various sections above are applicable to the other sections, mutatis mutandis. Thus, features specified in one section may be combined with features specified in other sections, as appropriate.

Other features and advantages of the present invention will become apparent from the following detailed description.