Antimicrobial analogues of Gramicidin S
Disclosed herein are N-aminated variants of Gramicidin S and methods of using the same for treating infections in a subject.
1. A method of preparing a compound of formula (I),
or a pharmaceutically acceptable salt thereof, comprising
removing amino protection groups from a compound of formula (I′) or a pharmaceutically acceptable salt thereof
wherein
R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen or —NH 2 ;
R 1A , R 2A , R 3A , and R 4A are each independently selected from hydrogen or —NH-G X ; and
G 1 , G 2 , and G x at each occurrence are independently amino protection groups;
wherein at least one of R 1 , R 2 , R 3 , and R 4 is —NH 2 .
2. The method of claim 1 , wherein R 3 is —NH 2 .
3. The method of claim 1 , wherein R 4 is —NH 2 .
4. The method of claim 1 , wherein two of R 1 , R 2 , R 3 , and R 4 are —NH 2 .
5. The method of claim 4 , wherein Wand R 3 are —NH 2 .
6. The method of claim 4 , wherein R 3 and R 4 are —NH 2 .
7. The method of claim 4 , wherein R 2 and R 3 are —NH 2 .
8. The method of claim 4 , wherein R 2 and R 4 are —NH 2 .
9. The method of claim 1 , wherein three of R 1 , R 2 , R 3 , and R 4 are —NH 2 .
10. The method of claim 9 , wherein R′, R 3 and R 4 are —NH 2 .
11. The method of claim 9 , wherein R 2 , R 3 and R 4 are —NH 2 .
12. The method of claim 1 , wherein each of R 2 , R 3 , and R 4 are —NH 2 .
13. The method of claim 1 , further comprising cyclizing a compound of formula (II) to the compound of formula (I′)
wherein R 1A , R 2A , R 3A , R 4A , G 1 and G 2 are defined as in claim 1 .
14. The method of claim 13 , further comprising preparing the compound of formula (II) from at least one building block selected from the group consisting of a dipeptide having a R 1A moiety, a dipeptide having a R 2A moiety, a dipeptide having a R 3A moiety, and a dipeptide having a R 4A moiety.
15. The method of claim 14 , wherein the preparation of the compound of formula (II) is carried out on a solid phase resin.
16. The method of claim 15 , wherein the solid phase resin is 2-chlorotrityl chloride resin.
17. The method of claim 14 , further comprising preparing the at least one building block.
18. The method of claim 1 , wherein at least one of G 1 , G 2 and G x is tert-butyloxycarbonyl (Boc).