Antibacterial therapeutics and prophylactics
The present disclosure relates generally to novel molecules, compositions, and formulations for treatment of bacterial infections in general and more specifically to bacterial infections with antibiotic resistant pathogens.
1. A compound of Formula (I):
wherein:
X is N or CRs;
R 1 is a cyclopropyl, or R 1 forms a link to R 2 to form a ring when X=CH;
R 2 is H, SH or alkyl;
R 3 is H or halo;
R 8 is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halo;
A is absent or a linker, wherein the linker is a bond or the linker is selected from the group consisting of:
unsubstituted piperazinyl; 3-methylamino piperidine; pyrrolidinyl [3,4-b]piperidine; piperind-4-ol; 1-H-benzoimidazol-2-yl; (1-H-benzoimidazol-2-yl)-amino; 2-Amino-1-H-benzoimidazolyl;
5,6-mono and di-substituted 1-H-benzoimidazol-2-yl optionally substituted with alkyl C 1 -C 11 alkyl, halo, nitro, carboxyl, amino, thiol, mono or di or polyguanidino group: —NH[C(M 1 )NHC(M 1 )] n -D (wherein M 1 is NH, O, S or CH; n is 1-10; D is NH 2 , COOH or CONH 2 ), amino acid analogues, spermine, norspermidine, spermidine analogues, guanidino amino acid, spermine linked through an amide linkage, norspermidine linked through an amide linkage, spermidine analogues linked through an amide linkage, or any combinations thereof; or
6-carboxyl-2-pyridyl ring; 5-Bromo-2-pyridyl ring or 5 or 6 mono or di-substituted 2-pyridyl ring wherein the 3, 4, 5 or 6 position of each can be independently substituted with a hydrogen atom, —CH 3 , CH 3 (CH 2 ) m — wherein m=1-10, halo, nitro, amino, carboxyl, methyl amino, thiol, —R 7 (CH 2 ) 0 NHCO—, —R 7 (CH 2 ) 0 CONH—, —R 7 (CH 2 ) 0 —OCO—, —R 7 (CH 2 ) 0 —COO—, or mono or di or polyguanidino group —NH[C(M 2 )NHC(M 2 )] t -D, an amino acid analogue, spermine, norspermidine, spermidine analogues, guanidino amino acid, spermine, norspermidine, or spermidine analogues through amide linkage, wherein R 7 =NH or S and o=0-10, M 2 =NH, oxygen atom, sulfur atom, or CH, D=NH 2 , COOH, CONH 2 , and t=1-10; wherein ‘A’ is functionalized with (CO—R L —CY′) q —Z′ or (CS—R 4 —CY′) q —Z′, wherein q is 1-10; R L is NH; Y′ is NH, O, S or CH; and Z′ is NH 2 , COOH, CONH 2 , OH, SH or alkyl group;
B is absent or a linker wherein the linker is a bond, or the linker is selected from the group consisting of a straight or branched alkyl chain, functionalized alkyl chain, alkyl chain with ester or amide linkages, —C(O)CH 2 —, —C(O)CH 2 NH—, —NHC(O)CH 2 —, —C(O)—, —C(O)NH(CH 2 ) r C(O)— (r is 1, 2, 3, 4 or 5), —CH═N—, —NH—, —OCH 2 CH 2 —, (OH)NHC(O)CH 2 , [(HO)NHC(O)]CH[{CH 3 (OH)}CH], [(HO)NHC(O)]CH[CH 2 (OH)CH], —CH 2 CH 2 NHCH 2 CH 2 —, or —CH 2 (CO)NH(CO)NH—Ar wherein ‘Ar’ represents aryl or phenyl substituted or not substituted, —CO-cysteine, —CO—(S-dodecane cysteine), —CO—S—(N-acetyl cysteine), and —CO—S—(N-acetyl dodecane cysteine); and
R 4 is a 5-membered aryl or heteroaryl, optionally substituted with 1 or 2 substituents; or R 4 is a 6-membered aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents; or R 4 is a fused ring 9-10-membered aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents; or R 4 is a fused ring 9-10-membered aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents, or R 4 is
where p is 0-10; M is CH, NH, or S; Y is NH, CH, O or S; L is a linker, wherein the linker is selected from the group consisting of amino, phenyl amino, substituted phenyl amino, straight or branched alkyl chain, —(CH 2 ) v —, (CH 2 ) v —NH—(CH 2 ) n , —CO(CH 2 ) v —R 5 , CO—C(NHCOCH 3 )—CH 2 SH—NH—, —O—, —S—, alkylene, —CO—, and —CONH, wherein R 5 =OH, NH 2 , N-alkyl amine, alkyl, thiol or any halogen atoms and v=0-10; and
Z is NH 2 , NHOH, OH, SH, alkyl, —COOH, or CONH 2 .
2. A compound selected from the group consisting of:
3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
4. A composition for topical application comprising the compound of claim 1 .
5. A composition for oral administration comprising the compound of claim 1 .
6. A composition for administration by injection comprising the compound of claim 1 .
7. A composition comprising a polymer matrix and the compound of claim 1 .
8. A method for treating an infection, the method comprising administering a therapeutically effective amount of the compound of claim 1 to a subject in need thereof.
9. The method of claim 8 , wherein said infection is caused by a resistant pathogen.
10. The method of claim 8 , wherein said infection is caused by a methicillin resistant or vancomycin-resistant pathogen.
11. The method of claim 8 , wherein said infection is caused by a quinolone resistant pathogen.
12. A method for wound treatment, the method comprising applying the compound of claim 1 to a wound.
13. A method for reducing infection caused by an implant, the method comprising applying the compound of claim 1 to the implant.
14. A method for reducing infection caused by an implant, the method comprising administering the compound of claim 1 to a subject in need thereof.
15. A method for the treatment of pneumonia, the method comprising administering the compound of claim 1 to a subject in need thereof.
16. A method for the treatment of urinary tract infection, the method comprising administering the compound of claim 1 to a subject in need thereof.
17. A method for the treatment of impetigo, the method comprising administering the compound of claim 1 to a subject in need thereof.
18. A method for the treatment of acne, the method comprising administering the compound of claim 1 to a subject in need thereof.
19. A method of inhibiting or reducing biofilm formation, the method comprising applying the compound of claim 1 to a surface or biofilm.
20. A compound which is: