Zwitterionic propargyl-linked antifolates useful for treating bacterial infections
The disclosure provides compounds of the formula I and the pharmaceutically acceptable salts thereof. The variables, e.g. R 1 , R 2 , R 3 , R 4 , A, B, J, V, W, M, J and Ar are defined herein. The disclosure also provides pharmaceutical compositions comprising a compound or salt of formula I and a pharmaceutically acceptable carrier, methods of inhibiting dihydrofolate reductase (DHFR) in vitro or in vivo with a compound or salt of formula I, and methods of treating a bacterial infections, fungal infections, and protozoal infections with a compound or salt of formula I. A compound or salt of formula I can be the first and only active ingredient used in a pharmaceutical composition or method of this disclosure or may be combined with one or more additional active ingredients that are not compounds or salts of formula I.
1. A compound of the formula I
or a pharmaceutically acceptable salt thereof, wherein:
R is H, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 1 , R 2 , R 3 , and R 4 are independently chosen from H, C 1 -C 6 alkyl, and cycloalkyl;
A and B are independently chosen from H, hydroxyl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
one of V and W is methoxy and the other is chosen from H, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
J and M are independently selected from H, halogen, hydroxyl, nitro, cyano, —COOH, —CHO, —CONH 2 , cycloalkyl, or C 1 -C 6 alkyl in which any methylene (—CH 2 ) is optionally replaced by O, NH, N(C 1 -C 6 alkyl), S, SO 2 , C(O)O, OC(O), or C(O), and which is optionally substituted with hydroxyl, amino, or halogen;
W and M may be joined to form a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring that contains 1, 2, or 3 heteroatoms independently chosen from N, O, and S; and
the Ar ring is a phenyl, pyridyl, or pyrimidinyl ring substituted with at least one —COOH, or —CH 2 COOH, group and optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein
R is methyl or ethyl;
A is hydrogen;
B is hydrogen or C 1 -C 6 alkyl; and
one of V and W is methoxy and the other is H.
3. The compound or pharmaceutically acceptable salt of claim 1 , wherein
R is methyl or ethyl;
A is hydrogen;
B is hydrogen or C 1 -C 6 alkyl; and
W and M are joined to form a 5-membered heterocyclic ring containing 2 oxygen atoms.
4. The compound or pharmaceutically acceptable salt of claim 1 , wherein
R 1 , R 2 , R 3 , and R 4 are H.
5. The compound or pharmaceutically acceptable salt claim 2 , wherein
J and M are independently selected from H, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
6. The compound or pharmaceutically acceptable salt of claim 1 , wherein A is H and B is methyl.
7. The compound or pharmaceutically acceptable salt of any one of claim 2 , wherein J and M are both H.
8. The compound or pharmaceutically acceptable salt of claim 1 , where the Ar ring is substituted with one —COOH substituent in the para position and optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
9. The compound or pharmaceutically acceptable salt of claim 1 , where the Ar ring is substituted with one —COOH substituent in the meta position and optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
10. The compound or pharmaceutically acceptable salt of claim 1 , where the Ar ring is substituted with one —COOH substituent in the ortho position and optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
11. The compound or pharmaceutically acceptable salt of claim 1 , wherein the Ar ring is a substituted phenyl ring.
12. A compound or pharmaceutically acceptable salt of of the formula I-A
(I-A) wherein the compound is selected from the compounds listed in
TABLE I
TABLE 1
Cpd
A
V
W
M
Ar
13
H
OCH 3
H
H
o-COOH phenyl
14
H
OCH 3
H
H
m-COOH phenyl
15
H
OCH 3
H
H
p-COOH phenyl
16
H
H
OCH 3
H
p-COOH phenyl
29
S—CH 3
OCH 3
H
H
p-COOH phenyl
30
R—CH 3
OCH 3
H
H
p-COOH phenyl
31
R—CH 3
H
OCH 3
H
p-COOH phenyl
32
S—CH 3
H
OCH 3
H
p-COOH phenyl
33
S—CH 3
OCH 3
H
H
p-COOCH 3 phenyl
34
R—CH 3
OCH 3
H
H
p-COOCH 3 phenyl
35
CH 3
H
—O—CH 2 —O—
36
CH 3
H
—O—CH 2 —O—
p-OH-phenyl
37
H
H
—O—CH 2 —O—
p-OH-phenyl
38
H
H
—O—CH 2 —O—
3-F,4-OH-phenyl
39
H
H
—O—CH 2 —O—
3,5-di-F,4-OH-phenyl
40
H
H
—O—CH 2 —O—
3,5-di-F,4-OCH 3 -phenyl
41
S—CH 3
H
—O—CH 2 —O—
p-COOH-phenyl
42
R—CH 3
H
—O—CH 2 —O—
p-COOH-phenyl
43
CH 3
H
—O—CH 2 —O—
2,3,5-tri-F,4-OH-phenyl
44
CH 3
H
—O—CH 2 —O—
2,3,5,6-tetra-F, 4-OH-
phenyl
45
CH 3
H
—O—CH 2 —O—
3-CN, 4-OH-phenyl
46
CH 3
H
—O—CH 2 —O—
4-CH 3 SO 2 HN-phenyl
47
CH 3
H
—O—CH 2 —O—
4-CH 3 HNSO 2 -phenyl
48
CH 3
H
—O—CH 2 —O—
49
CH 3
H
—O—CH 2 —O—
50
CH 3
H
—O—CH 2 —O—
3,4,-di-OH-phenyl
51
CH 3
H
—O—CH 2 —O—
52
H
H
OMe
H
53
H
H
OMe
H
54
CH
H
—O—CH 2 —O—
55
R—CH 3
H
—O—CH 2 —O—
pyrid-4-yl
56
H
OCH 3
H
H
57
R—CH 3
OCH 3
H
H
pyrid-4-yl
58
R—CH 3
H
OCH 3
H
p-COOH phenyl
59
H
H
OCH 3
H
p-COOH phenyl
60
H
H
OCH 3
OCH 3
4-Pyridyl
13. The compound or pharmaceutically acceptable salt of claim 12 , wherein the compound is
14. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable carrier.
15. A method of treating a bacterial infection or a fungal infection in a patient comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the patient.
16. The method of claim 15 , additionally comprising administering an additional antibacterial compound that is not a compound of formula I or salt thereof to the patient.
17. The method of claim 15 , wherein the bacterial infection is a Gram negative bacterial infection.
18. The method of claim 15 , wherein the bacterial infection is a S. aureus infection.