Antibacterial compounds targeting isoprenoid biosynthesis

Patent metadata

Field	Value
Publication number	US-2016039857-A1
Application number	US-201314649153-A
Country	US
Kind code	A1
Filing date	Dec 4, 2013
Priority date	Dec 4, 2012
Publication date	Feb 11, 2016
Grant date	—

Abstract

With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. The invention provides small molecules that inhibit cellular drug targets such as UPPS and FPPS by interacting with binding pockets, thereby preventing enzyme function. Compounds described herein are also active against Staphylococcus aureus (MIC90˜0.25 μg/mL), can potently synergize with methicillin (fractional inhibitory concentration index=0.25), and are protective in a mouse infection model. The invention therefore provides numerous compounds for anti-bacterial treatments and for restoring sensitivity to drugs such as methicillin, using combination therapies.

First claim

1 . A method of killing or inhibiting the growth of methicillin-resistant Staphylococcus aureus (MRSA) comprising contacting the MRSA with an effective lethal or inhibitory amount of a bisphenylamidine or bisphenylalkyne compound that binds to site 4 of bacterial undecaprenyl diphosphate synthase (UPPS), and further comprising contacting the MRSA with an effective lethal or inhibitory amount of methicillin, wherein the bisphenylamidine or bisphenylalkyne compound comprises:
(a) two moieties of Formula I:

or
(b) two moieties of Formula II:

wherein the moieties of Formula I are connected by a linker comprising a phenyl moiety at the amide carbonyl, or the moieties of Formula II are connected by a linker comprising a phenyl moiety at the distal carbon of the phenylalkyne, each phenyl of Formula I or Formula II is optionally substituted, each moiety of Formula I or Formula II includes at least one heterocycle or imidamide substituent, wherein the heterocycle or imidamide substituent is optionally linked to the Formula I or Formula II moiety through a linker comprising one to about 10 carbon atoms, and wherein the compound has a molecular weight of at least about 300 and less than about 1,200;
thereby killing or inhibiting the growth of the MRSA.

2 . The method of claim 1 wherein the bisphenylamidine or bisphenylalkyne compound additionally binds to site 1, site 2, or site 3, or a combination thereof, of UPPS.

3 . The method of claim 1 wherein the bisphenylamidine or bisphenylalkyne compound does not bind to site 1 of UPPS.

4 . The method of claim 1 wherein the bisphenylamidine or bisphenylalkyne compound inhibits UPPS with an IC 50 value of less than about 1 μM.

5 . The method of claim 1 wherein the bisphenylamidine or bisphenylalkyne compound inhibits UPPS with an IC 50 value of less than about 150 nM.

6 . The method of claim 1 wherein the linker is an optionally substituted phenyl, biphenyl, naphthyl, fluorene, carbazole, diphenyl ether, 1,3-diphenylurea, vinylbenzene, divinylbenzene, or phenylethyl.

7 . The method of claim 1 wherein the compound is a compound of Formula III:

wherein
each R 1 is independently an oxygen heterocycle, a nitrogen heterocycle or an imidamide;
each R 2 is independently hydrogen, amide, alkylamide, or a nitrogen heterocycle optionally linked by a phenyl, urea, or phenylurea;
each R 3 is independently hydrogen, alkyl, alkoxy, hydroxy, amino, nitro, halo, or an optionally substituted phenylamide; and
each n is independently 1 or 2;

or a salt or solvate thereof.

8 . The method of claim 1 wherein the compound is a compound of Formula IV:

wherein
X is CH 2 , O, NH, S, SO 2 , NH—(C═O)—NH, a direct bond, or absent;
Y is CH 2 , O, NH, S, SO 2 , a direct bond, or absent;
each R 1 is independently an oxygen heterocycle, a nitrogen heterocycle or an imidamide;
each R 2 is independently hydrogen, amide, alkylamide, or a nitrogen heterocycle optionally linked by a phenyl, urea, or phenylurea;
each R 3 is independently hydrogen, alkyl, alkoxy, hydroxy, amino, nitro, halo, or an optionally substituted phenylamide; and
each n is independently 1 or 2;

or a salt or solvate thereof.

9 . The method of claim 1 wherein the compound is a compound of Formula V:

wherein
each R s is independently a saccharide moiety;
each R 3 is independently hydrogen, alkyl, alkoxy, hydroxy, amino, nitro, halo, or an optionally substituted phenylamide; and
n is independently 1, 2, 3, or 4;

or a salt or solvate thereof.

10 . The method of claim 9 wherein the compound of Formula V is:

or a salt or solvate thereof.

11 . The method of claim 1 wherein the compound that includes two moieties of Formula I is:

wherein each n is individually 1, 2, or 3;
or a salt thereof.

12 . The method of claim 7 wherein the compound of Formula III is:

wherein each n is individually 1, 2, or 3;
or a salt thereof.

13 . The method of claim 8 wherein the compound of Formula IV is:

wherein each n is individually 1, 2, or 3;
or a salt or solvate thereof.

14 . A compound of Formula V:

wherein
each R s is independently a saccharide moiety;
each R 3 is independently hydrogen, alkyl, alkoxy, hydroxy, amino, nitro, halo, or an optionally substituted phenylamide; and
n is independently 1, 2, 3, or 4;
or a salt or solvate thereof.

15 . The compound of claim 14 wherein the compound of Formula V is:

or a salt or solvate thereof.

16 . A pharmaceutical composition comprising a compound of claim 14 in combination with a pharmaceutically acceptable carrier or excipient.

17 . A compound of Formula VI:

wherein
R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, alkyl, alkoxy, hydroxy, amino, nitro, halo, or an optionally substituted phenylamide; and
n is 0, 1, or 2;

or a salt thereof.

18 . The compound of claim 17 wherein the compound of Formula VI is:

or a salt or solvate thereof.

19 . A pharmaceutical composition comprising a compound of claim 17 in combination with a pharmaceutically acceptable carrier or excipient.

20 . (canceled)

Assignees

• Univ Illinois
• Univ California

Inventors

• Zhu Wei
• Lindert Steffen
• Zhang Yonghui
• Sinko William
• Li Kai
• Mccammon James Andrew
• Oldfield Eric

Classifications

• C07D243/04

  having the nitrogen atoms in positions 1 and 3 · CPC title

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K31/7034

  attached to a carbocyclic compound, e.g. phloridzin · CPC title

• C07D233/24

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07H15/203

  Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems · CPC title