Cleavable conjugates of antibiotics and an antibacterial cell-penetrating peptide
The present disclosure relates to novel cleavable conjugates of antibiotics and an antibacterial cell-penetrating peptide, and methods to make and use the novel cleavable conjugates of antibiotics and an antibacterial cell-penetrating peptide.
1. A compound of Formula:
or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, derivative thereof, wherein
R 1 is an antibiotic moiety;
R 2 and R 3 are each independently H, a C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;
R 4 is H, a C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;
L 3 is C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;
Z is a linker comprising a disulfide bond (S—S bond); and
n is 3-8.
2. A compound of claim 1 , wherein the compound is:
or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, derivative or prodrug thereof, wherein
R 1 is an antibiotic moiety;
R 2 and R 3 are each independently H, a C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;
R 4 is H, a C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;
L 1 , L 2 , L 3 are each independently C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;
X is O or NR 5 , wherein R 5 is H, C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl, or X combined with R 1 together is an antibiotic moiety; and
n is 3-8.
3. The compound of claim 1 , wherein R 1 or R 1 —X represents the moiety of an aminoglycoside antibiotics or any derivative thereof.
4. The compound of claim 1 , wherein R 1 or R 1 —X represents an antibiotic moiety, wherein the antibiotic moiety is of an antibiotics selected from the group consisting of Gentamicin, Streptomycin, Kanamycin, Fradiomyctn, Paromomycin, Tobramycin, Netilmicin, Amikacin, Neomycin, Ribostamycin, Dibekacin, Sisomicin, Isepamicin, Bekanamycin, Astromicin, Plazomicin, Vancomycin, Linezolid, Erythromycin, Eperezolid, and any derivative thereof.
5. The compound of claim 1 , wherein R 2 and R 3 are each independently C 1 -C 4 branched or unbranched alkyl chain.
6. The compound of claim 1 , wherein R 2 and R 3 are isobutyl group.
7. The compound of claim 1 , wherein R 4 is hydrogen.
8. The compound of claim 2 , wherein L 1 is (CH 2 ) 3 —, L 2 is (CH 2 ) 3 —, and L 3 is —(CH 2 )—.
9. The compound of claim 1 , wherein R 1 represents an antibiotic moiety, and the antibiotic moiety is of an antibiotics selected from the group consisting of Gentamicin, Streptomycin, Kanamycin, Fradiomyctn, Paromomycin, Tobramycin, Netilmicin, Amikacin, Neomycin, Ribostamycin, Dibekacin, Sisomicin, Isepamicin, Bekanamycin, Astromicin, Plazomicin, Vancomycin, Linezolid, Erythromycin, Eperezolid, and any derivative thereof; R 2 and R 3 are isobutyl group; R 4 is hydrogen; L 1 is —(CH 2 ) 3 —, L 2 is —(CH 2 ) 3 —, and L 3 is —(CH 2 )—; X is O; and n is 4.
10. The compound of claim 2 wherein, R 1 or R 1 —X represents an aminoglycoside antibiotics moiety, and the aminoglycoside antibiotics is selected from the group consisting of Gentamicin, Kanamycin, Tobramycin, Amikacin, Neomycin, Plazomicin, and any derivative thereof; R 2 and R 3 are isobutyl group; R 4 is hydrogen; L 1 is —(CH 2 ) 3 —, L 2 is —(CH 2 ) 3 —, and L 3 is —(CH 2 )—; X is O; and n is 4.
11. The compound of claim 2 , wherein R 1 or R 1 —X represents Kanamycin moiety or any derivative thereof; R 2 and R 3 are isobutyl group; R 4 is hydrogen; L 1 is —(CH 2 ) 3 —, L 2 is —(CH 2 ) 3 —, and L 3 is —(CH 2 )—; X is O; and n is 4.
12. The compound of claim 11 , wherein the compound is:
or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, derivative thereof.
13. The compound of claim 2 , wherein R 1 or R 1 —X represents Tobramycin moiety or any derivative thereof.
14. The compound of claim 13 , wherein the compound is:
or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, derivative thereof.