Isothiocyanate compounds, pharmaceutical compositions, and uses thereof
View Patent ↗Provided herein are compositions of matter and pharmaceutical compositions thereof, for use in inhibiting the growth of various microbial pathogens, including bacteria, fungi, protozoa, and viral pathogens. Also provided herein are methods of treating microbial diseases/infections and cancer with the compositions. The compositions are additionally useful in wood preservation and food preservation by inhibition of microbial growth.
1. A method of treating a subject infected with a a bacterium, the method comprising delivering to a subject an anti-microbially effective amount of a composition comprising a compound of formula I:
S═C═N—(R) b —(X) a —(R) c —N═C═S (I)
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein:
a, b, and c are independently 0 or 1, provided that a, b, and c are not all 0, and that b and c are not both 0;
X is an aryl ring system unsubstituted or substituted with from 1 to 4 moieties independently selected from —Br, —Cl, —OH, —NH 2 , —COOH, OR′—CH 3 or R″—CH 3 wherein R′ and R″, independently, are an alkylene moiety having the formula —(CH 2 ) n —, where n is 0 or an integer from 1 to 3; and
each R is independently selected from the group consisting of linear or branched alkylene moieties having from 1 to 10 C atoms and linear or branched heteroalkylene moieties having from 2 to 10 C atoms and from 1 to 3 O atoms.
2. The method of claim 1 , wherein the bacterium is a gram-positive bacterium.
3. The method of claim 1 , wherein the bacterium is a drug resistant bacterium.
4. The method of claim 1 , wherein the delivering further comprises delivering to a subject one or more additional anti-microbial compositions.
5. A method of inhibiting the growth of a bacterial cell, the method comprising contacting the bacterial cell with a growth-inhibitory amount of a composition comprising a compound of formula I:
S═C═N—(R) b —(X) a —(R) c —N═C═S (I)
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein:
a, b, and c are independently 0 or 1, provided that a, b, and c are not all 0, and that b and c are not both 0;
X is an aryl ring system unsubstituted or substituted with from 1 to 4 moieties independently selected from —Br, —Cl, —OH, —NH 2 , —COOH, OR′—CH 3 or R″—CH 3 wherein R′ and R″, independently, are an alkylene moiety having the formula —(CH 2 ) n —, where n is 0 or an integer from 1 to 3; and
each R is independently selected from the group consisting of linear or branched alkylene moieties having from 1 to 10 C atoms and linear or branched heteroalkylene moieties having from 2 to 10 C atoms and from 1 to 3 O atoms.
6. The method of claim 1 , wherein a=0, and each R is independently C 1 -C 10 alkylene.
7. The method of claim 1 , wherein a=0, b=0, c=1, and R is C 1 -C 10 alkylene.
8. The method of claim 1 , wherein a=0, b=0, c=1, and R is C 4 -C 8 alkelene.
9. The method of claim 1 , wherein a=1, X is phenylene, b and c are independently 1 or 0, and each R is independently C 1 -C 4 alkylene.
10. The method of claim 9 , wherein each R is methylene.
11. The method of claim 1 , wherein the compound of formula I is selected from the group consisting of S═C═N—(CH 2 ) 4 —N═C═S, S═C═N—(CH 2 ) 5 —N═C═S, S═C═N—(CH 2 ) 6 —N═C═S, S═C═N—(CH 2 ) 7 —N═C═S, S═C═N—(CH 2 ) 8 —N═C═S, S═C═N—(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —N═C═S, S═C═N—CH 2 —C 6 H 4 —CH 2 —N═C═S, and S═C═N—CH 2 —C 6 H 4 —N═C═S.
12. The method of claim 11 , wherein the bacterium is a Gram-positive bacterium selected from the group consisting of Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Staphylococcus epidermis, Staphylococcus aureus, Streptococcus pyogenes, Enterococcus faecium, Enterococcus faecalis, Mycobacterium tuberculosis, Mycobacterium avium , and Mycobacterium bovis.
13. The method of claim 11 , wherein the bacterium is a drug resistant bacterium selected from the group consisting of Methicillin resistant Staphylococcus aureus , Erythromycin resistant Staphylococcus aureus , Oxacillin/Gentamycin resistant Staphylococcus aureus , Vancomycin/Oxacillin resistant Staphylococcus aureus , Gentamycin resistant Enterococcus faecium , Vancomycin resistant Entercoccus faecium , Ampicillin-resistant Enterococcus faecium , Gentamycin resistant Enterococcus faecalis , Vancomycin resistant Entercoccus faecalis , Ampicillin-resistant Enterococcus faecalis , Rifampicin resistant Mycobacterium tuberculosis , Isoniazid resistant Mycobacterium tuberculosis , multidrug resistant Mycobacterium tuberculosis , and Rifampicin resistant Mycobacterium bovis.
14. The method of claim 2 , wherein the Gram-positive bacterium is selected from the group consisting of Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Staphylococcus epidermis, Staphylococcus aureus, Streptococcus pyogenes, Enterococcus faecium, Enterococcus faecalis, Mycobacterium tuberculosis, Mycobacterium avium , and Mycobacterium bovis.
15. The method of claim 3 , wherein the drug resistant bacterium is selected from the group consisting of Methicillin resistant Staphylococcus aureus , Erythromycin resistant Staphylococcus aureus , Oxacillin/Gentamycin resistant Staphylococcus aureus , Vancomycin/Oxacillin resistant Staphylococcus aureus , Gentamycin resistant Enterococcus faecium , Vancomycin resistant Entercoccus faecium , Ampicillin-resistant Enterococcus faecium , Gentamycin resistant Enterococcus faecalis , Vancomycin resistant Entercoccus faecalis , Ampicillin-resistant Enterococcus faecalis , Rifampicin resistant Mycobacterium tuberculosis , Isoniazid resistant Mycobacterium tuberculosis , multidrug resistant Mycobacterium tuberculosis , and Rifampicin resistant Mycobacterium bovis.
16. The method of claim 5 , wherein the bacterial cell is a gram-positive bacterial cell.
17. The method of claim 16 , wherein the gram-positive bacterium is selected from the group consisting of: Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Staphylococcus epidermis, Staphylococcus aureus, Streptococcus pyogenes, Enterococcus faecium, Enterococcus faecalis, Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium bovis.
18. The method of claim 5 , wherein the bacterial cell is a drug resistant bacterial cell.
19. The method of claim 18 , wherein the drug resistant bacterial cell is Methicillin resistant Staphylococcus aureus , Erythromycin resistant Staphylococcus aureus , Oxacillin/Gentamycin resistant Staphylococcus aureus , Vancomycin/Oxacillin resistant Staphylococcus aureus , Gentamycin resistant Enterococcus faecium , Vancomycin resistant Entercoccus faecium , Ampicillin-resistant Enterococcus faecium , Gentamycin resistant Enterococcus faecalis , Vancomycin resistant Entercoccus faecalis , Ampicillin-resistant Enterococcus faecalis , Rifampicin resistant Mycobacterium tuberculosis , Isoniazid resistant Mycobacterium tuberculosis , multidrug resistant Mycobacterium tuberculosis , and Rifampicin resistant Mycobacterium bovis.