Anti-bacterial stilbene derivatives and methods of use

Patent metadata

Field	Value
Publication number	US-12286398-B2
Application number	US-202017604908-A
Country	US
Kind code	B2
Filing date	Apr 17, 2020
Priority date	Apr 19, 2019
Publication date	Apr 29, 2025
Grant date	Apr 29, 2025

Abstract

Provided herein are novel antibacterial compounds of Formula I. The compounds can be made through enzymatic oxidative dimerization in the presence of a suitable organism and one or more metal salts. Pathogenic bacteria exposed to the compound of Formula I do not develop resistance to these compounds even after prolonged exposure. Also provided herein are methods of treating bacterial infections, and method of killing or disinfecting bacteria.

First claim

What is claimed is:

1. A compound of Formula I, or a salt, solvate, tautomer, enantiomer, or geometric isomer thereof:

wherein:
at each occurrence R 1 , R 2 , R 3 , R 4 , R 5 , A 1 , A 2 , A 3 , A 4 , A 5 , A 1′ , A 2′ , A 3′ , A 4′ , and A 5′ is independently selected from hydrogen, F, Cl, Br, I, OR, OC(O)N(R) 2 , CN, NO, NO 2 , ONO 2 , azido, CF 3 , OCF 3 , R, methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R) 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R) 2 , N(R)C(S)N(R) 2 , N(COR)COR, N(OR)R, C(═NH)N(R) 2 , C(O)N(OR)R, and C(═NOR)R;
at each occurrence R 6 is independently selected from hydrogen, CF 3 , R, methylenedioxy, ethylenedioxy, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 ) 1-2 N(R)C(O)R, (CH 2 ) 1-2 N(R)N(R) 2 , C(═NH)N(R) 2 , C(O)N(OR)R, and C(═NOR)R; and
at each occurrence R is independently hydrogen, (C 1 -C 100 ) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl.

2. The compound of claim 1 , wherein the compound is of Formula II, or a salt, solvate, tautomer, enantiomer, or geometric isomer thereof:

wherein at each occurrence R 7 and R 8 are independently selected from hydrogen, CF 3 , R, methylenedioxy, ethylenedioxy, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 ) 1-2 N(R)C(O)R, (CH 2 ) 1-2 N(R)N(R) 2 , C(═NH)N(R) 2 , C(O)N(OR)R, and C(═NOR)R.

3. The compound of claim 1 , wherein the compound is of Formula III, or a salt, solvate, tautomer, enantiomer, or geometric isomer thereof:

4. The compound of claim 3 , wherein at least one of A 1 , A 2 , A 3 , A 4 , A 5 , A 1′ , A 2′ , A 3′ , A 4′ , and A 5′ is not hydrogen.

5. The compound of claim 1 , wherein A 1 and A 1′ are the same, A 2 and A 2′ are the same, A 3 and A 3′ are the same, A 4 and A 4′ are the same, and A 5 and A 5′ are the same.

6. The compound of claim 1 , wherein at least one of the following applies:
A 1 , A 2 , A 3 , A 4 , and A 5 are hydrogen;
R 3 and R 5 are isopropyl;
R 1 and R 4 are OH;
R 3 and R 5 are hydrogen;
A 3 and A 3′ are OH.

7. The compound of claim 1 , which is selected from the group consisting of:

8. A pharmaceutical composition comprising the compound of claim 1 , or a salt, solvate, tautomer, enantiomer, or geometric isomer thereof, and at least one pharmaceutically acceptable excipient.

9. A method of making a compound of Formula Ia, the method comprising:
contacting a compound of Formula IV, or a salt, solvate, tautomer, enantiomer, or geometric isomer thereof:

with a medium comprising an organism and at least one metal salt, to yield a compound of Formula Ia, or a salt, solvate, tautomer, enantiomer, or geometric isomer thereof:

wherein:
at each occurrence R 2 , R 3 , A 1 , A 2 , A 3 , A 4 , and A 5 , is independently selected from hydrogen, F, Cl, Br, I, OR, OC(O)N(R) 2 , CN, NO, NO 2 , ONO 2 , azido, CF 3 , OCF 3 , R, methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R) 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R) 2 , N(R)C(S)N(R) 2 , N(COR)COR, N(OR)R, C(═NH)N(R) 2 , C(O)N(OR)R, and C(═NOR)R; and
at each occurrence R is independently hydrogen, (C 1 -C 100 ) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl.

10. The method of claim 9 , wherein the organism comprises a transformed organism containing a Plu1886 gene.

11. The method of claim 10 , wherein at least one of the following applies:
the transformed organism is E. coli BL21 (DE3);
the Plu1886 gene is from P. luminescens.

12. The method of claim 9 , wherein at least one of the following applies:
the metal salt is a salt of Li, Na, K, Cs, Mg, Ca, Sr, Ba, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Ru, Rh, Pd, Ag, W, Re, Os, Ir, Pt, or Au;
the salt is a chloride, bromide, iodide, fluoride, sulfate (SO 4 2− ), phosphate (PO 4 2− ), nitrate, or carbonate;
the metal salt is at least one salt selected from NiCl 2 , CaCl 2 , FeSO 4 , CuSO 4 , ZnSO 4 , CoCl 2 , MgSO 4 , or MnCl 2 .

13. The method of claim 9 , wherein the medium comprises
(a) a buffer, or
(b) a gastrointestinal tract of a subject, wherein the organism comprises a bacterial population in the subject, and wherein the metal salt comprises a metal salt in the gastrointestinal tract of the subject.

14. A method of killing or disinfecting bacteria, the method comprising:
contacting a bacterial population with a compound of Formula I, or a salt, solvate, tautomer, enantiomer, or geometric isomer thereof:

wherein:
at each occurrence R 1 , R 2 , R 3 , R 4 , R 5 , A 1 , A 2 , A 3 , A 4 , A 5 , A 1′ , A 2′ , A 3′ , A 4′ , and A 5′ is independently selected from hydrogen, F, Cl, Br, I, OR, OC(O)N(R) 2 , CN, NO, NO 2 , ONO 2 , azido, CF 3 , OCF 3 , R, methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R) 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R) 2 , N(R)C(S)N(R) 2 , N(COR)COR, N(OR)R, C(═NH)N(R) 2 , C(O)N(OR)R, and C(═NOR)R;
at each occurrence R 6 is independently selected from hydrogen, CF 3 , R, methylenedioxy, ethylenedioxy, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 ) 1-2 N(R)C(O)R, (CH 2 ) 1-2 N(R)N(R) 2 , C(═NH)N(R) 2 , C(O)N(OR)R, and C(═NOR)R; and
at each occurrence R is independently hydrogen, (C 1 -C 100 ) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl;

wherein the bacterial population is killed or disinfected after coming into contact with the compound of Formula I, or salt, solvate, tautomer, enantiomer, or geometric isomer thereof.

15. The method of claim 14 , wherein the bacterial population comprises a pathogenic bacterial population that is pathogenic in a mammal.

16. The method of claim 14 , wherein at least one the following applies:
the bacterial population comprises at least one bacterial genus selected from Bacillus, Bartonella, Bordetella, Borrelia, Brucella, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Corynebacterium, Enterococcus, Escherichia, Francisella, Haemophilus

Assignees

• Univ Yale

Inventors

• Crawford Jason
• Goddard Tyler
• Park Hyun Bong
• Patel Jaymin

Classifications

• A61K9/0014

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title

• A01N35/06

  containing keto or thioketo groups as part of a ring, e.g. cyclohexanone, quinone; Derivatives thereof, e.g. ketals · CPC title

• A01P1/00

  Disinfectants; Antimicrobial compounds or mixtures thereof · CPC title

• A61P31/02

  Local antiseptics · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title