Anti-cancer and anti-microbial oxazolidinones
Disclosed herein are various novel oxazolidinone, imidazolidinone, and thiazolidinone analogs and methods of treating cancer and/or microbial infection using these analogs. Particular 4-oxazolidinone compounds are shown to have anti-cancer and anti-microbial activity.
1. A method of treating an individual infected with a bacterium, comprising: administering to the individual a compound having the structure of formula I:
and pharmaceutically acceptable salts or prodrugs thereof, wherein:
R 1 and R 2 are separately selected, wherein one of R 1 and R 2 is a molecular fragment having the structure of formula (II),
Z is selected from the group consisting of O, S, and NR 5 ;
R 6 and R 7 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl;
R 8 and R 9 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; and halogenated alkyl including polyhalogenated alkyl; or are separately absent;
R 10 and R 11 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl; or are separately absent;
and the remaining substituent of R 1 and R 2 is selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; heteroaryl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl;
R 3 is ═O;
R 1′ is selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl; or are separately absent;
R 2′ is selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; heteroaryl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl; or are separately absent;
Y is separately selected from the group consisting of O, S, and NR 5 ;
R 4 and each R 5 are separately selected from the group consisting of hydrogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 aminoalkyl, C 2-6 haloalkyl, C 1-6 alkoxycarbonyl, and C 2-6 hydroxyalkyl; C 3-8 cycloalkyl; —C(O)—C 5-6 aryl substituted with C 1-3 alkyl or halo; C 5-6 aryl; C 5-6 heteroaryl; C 5-6 cycloalkyl; and C 5-6 heterocycloalkyl, or are separately absent;
any bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;
any bond represented by a single dashed line is a single bond or is absent; and
any carbon-carbon double bond has a configuration selected from the group consisting of cis and trans.
2. The method of claim 1 , wherein the bacterium is a Gram-positive bacterium.
3. The method of claim 1 , wherein the bacterium is selected from one or more of Staphylococcus aureus (methicillin sensitive), Staphylococcus aureus (methicillin resistant), Streptococcus pneumonia (penicillin sensitive), Streptococcus pneumonia (penicillin resistant), Staphylococcus epidermis (multiple drug resistant), Enterococcus faecalis (vancomycin sensitive), Enterococcus faecium (vancomycin resistant), and Haemophilus influenzae.
4. The method of claim 1 , wherein the compound has the structure of formula VI, wherein the crossed double bond indicates that the double bond may have either trans or cis geometry:
5. The method of claim 1 , wherein the compound has the structure of formula VII, wherein the crossed double bond indicates that the double bond may have either trans or cis geometry:
6. The method of claim 1 , wherein the compound has the structure of formula VIII, wherein the crossed double bond indicates that the double bond may have either trans or cis geometry:
7. A method of treating an individual infected with a bacterium, comprising: administering to the individual a compound having the structure of formula III:
and pharmaceutically acceptable salts or prodrugs thereof, wherein:
Y is selected from the group consisting of O, S, and NR 5 ;
R 2 , R 6 , and R 7 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl;
R 2′ is selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl; or is absent;
R 4 and R 5 are separately selected from the group consisting of hydrogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 aminoalkyl, C 2-6 haloalkyl, C 1-6 alkoxycarbonyl, and C 2-6 hydroxyalkyl; C 3-8 cycloalkyl; —C(O)—C 5-6 aryl substituted with C 1-3 alkyl or halo; C 5-6 aryl; C 5-6 heteroaryl; C 5-6 cycloalkyl; and C 5-6 heterocycloalkyl or are separately absent;
R 8 , R 9 , R 10 , and R 11 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl; or are separately absent;
any bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;
any bond represented by a single dashed line is a single bond or is absent; and
any carbon-carbon double bond has a configuration selected from the group consisting of cis and trans.
8. The method of claim 7 , wherein the bacterium is a Gram-positive bacterium.
9. The method of claim 7 , wherein the bacterium is selected from one or more of Staphylococcus aureus (methicillin sensitive), Staphylococcus aureus (methicillin resistant), Streptococcus pneumonia (penicillin sensitive), Streptococcus pneumonia (penicillin resistant), Staphylococcus epidermis (multiple drug resistant), Enterococcus faecalis (vancomycin sensitive), Enterococcus faecium (vancomycin resistant), and Haemophilus influenzae.
10. A method of treating an individual infected with a bacterium, comprising: administering to the individual compound having the structure of formula IV:
and pharmaceutically acceptable salts or prodrugs thereof, wherein:
R 2 , R 6 , and R 7 are separately selected from the group consisting of mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl;
R 2′ is selected from the group consisting of hydrogen and mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl;
R 4 is selected from the group consisting of hydrogen, straight- or branched-chain C 1-6 alkyl, straight- or branched-chain C 2-6 alkenyl, and straight- or branched-chain C 2-6 alkynyl, or is absent;
any bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond with the proviso that such bonds in the compound of formula IV may not both be double bonds; and
any carbon-carbon double bond has a configuration selected from the group consisting of cis and trans.
11. The method of claim 10 , wherein the bacterium is a Gram-positive bacterium.
12. The method of claim 10 , wherein the bacterium is selected from one or more of Staphylococcus aureus (methicillin sensitive), Staphylococcus aureus (methicillin resistant), Streptococcus pneumonia (penicillin sensitive), Streptococcus pneumonia (penicillin resistant), Staphylococcus epidermis (multiple drug resistant), Enterococcus faecalis (vancomycin sensitive), Enterococcus faecium (vancomycin resistant), and Haemophilus influenzae.
13. A method of treating an individual infected with a bacterium, comprising: administering to the individual a compound having the structure of formula V:
and pharmaceutically acceptable salts or prodrugs thereof, wherein:
Y is selected from the group consisting of O and NR 5 ;
Z is selected from the group consisting of O, S, and NR 5 ;
R 2 , R 6 , and R 7 are separately selected from the group consisting of hydrogen;
halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl;
R 2′ is selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl; or is absent;
R 4 and each R 5 are separately selected from the group consisting of hydrogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 aminoalkyl, C 2-6 haloalkyl, C 1-6 alkoxycarbonyl, and C 2-6 hydroxyalkyl; C 3-8 cycloalkyl; —C(O)—C 5-6 aryl substituted with C 1-3 alkyl or halo; C 5-6 aryl; C 5-6 heteroaryl; C 5-6 cycloalkyl; and C 5-6 heterocycloalkyl or are separately absent;
R 8 and R 9 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; and halogenated alkyl including polyhalogenated alkyl; or are separately absent;
R 10 and R 11 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl; or are separately absent;
R 6 and R 8 are optionally bound together to form an optionally substituted ring;
any bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;
any bond represented by a single dashed line is a single bond or is absent; and
any carbon-carbon double bond has a configuration selected from the group consisting of cis and trans.
14. The method of claim 13 , wherein the bacterium is a Gram-positive bacterium.
15. The method of claim 13 , wherein the bacterium is selected from one or more of Staphylococcus aureus (methicillin sensitive), Staphylococcus aureus (methicillin resistant), Streptococcus pneumonia (penicillin sensitive), Streptococcus pneumonia (penicillin resistant), Staphylococcus epidermis (multiple drug resistant), Enterococcus faecalis (vancomycin sensitive), Enterococcus faecium (vancomycin resistant), and Haemophilus influenzae.
16. A method of treating an individual infected with a bacterium, comprising: administering to the individual a compound having the structure of formula V:
and pharmaceutically acceptable salts or prodrugs thereof, wherein:
Y is selected from the group consisting of O, S, and NR 5 ;
Z is selected from the group consisting of O, S, and NR 5 ;
R 2 , R 6 , and R 7 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl;
R 2′ is selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl; or is absent;
R 4 and each R 5 are separately selected from the group consisting of hydrogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 aminoalkyl, C 2-6 haloalkyl, C 1-6 alkoxycarbonyl, and C 2-6 hydroxyalkyl; C 3-8 cycloalkyl; —C(O)—C 5-6 aryl substituted with C 1-3 alkyl or halo; C 5-6 aryl; C 5-6 heteroaryl; C 5-6 cycloalkyl; and C 5-6 heterocycloalkyl or are separately absent;
R 8 and R 9 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; and halogenated alkyl including polyhalogenated alkyl; or are separately absent;
R 10 and R 11 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl; or are separately absent;
R 6 and R 8 are optionally bound together to form an optionally substituted ring, provided that if R 6 and R 8 together form an aryl, then at least one of R 2 , R 4 , and R 11 is not hydrogen;
any bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;
any bond represented by a single dashed line is a single bond or is absent; and
any carbon-carbon double bond has a configuration selected from the group consisting of cis and trans.
17. The method of claim 16 , wherein the bacterium is a Gram-positive bacterium.
18. The method of claim 16 , wherein the bacterium is selected from one or more of Staphylococcus aureus (methicillin sensitive), Staphylococcus aureus (methicillin resistant), Streptococcus pneumonia (penicillin sensitive), Streptococcus pneumonia (penicillin resistant), Staphylococcus epidermis (multiple drug resistant), Enterococcus faecalis (vancomycin sensitive), Enterococcus faecium (vancomycin resistant), and Haemophilus influenzae.