阅读说明：本技术 氰基亚胺噻唑烷呋喃甲酰胺类化合物在制备β-葡萄糖醛酸苷酶抑制剂中的应用 (Application of cyanoimine thiazolidine furan carboxamide compound in preparation of β -glucuronidase inhibitor ) 是由 王鸿 崔紫宁 魏斌 周涛顺 于 2020-05-14 设计创作，主要内容包括：本发明公开了一种氰基亚胺噻唑烷呋喃甲酰胺类化合物在制备β-葡萄糖醛酸苷酶抑制剂中的应用,本发明氰基亚胺噻唑烷呋喃甲酰胺类化合物对大肠杆菌β-葡萄糖醛酸苷酶(EcGUS)抑制活性十分显著,IC<Sub>50</Sub>值范围为1.2μM-23.1μM,在治疗伊立替康或非甾体类抗炎药引起的药源性腹泻的药物的研发方面具有广阔的应用前景。(The invention discloses an application of a cyanoimine thiazolidine furoylamide compound in preparing β -glucuronidase inhibitor, the cyanoimine thiazolidine furoylamide compound has very obvious inhibition activity on Escherichia coli β -glucuronidase (EcGUS), and IC is 50 The value range is 1.2 mu M-23.1 mu M, and the compound has wide application prospect in the aspect of research and development of medicaments for treating drug-induced diarrhea caused by irinotecan or non-steroidal anti-inflammatory drugs.)

1. An application of a cyanoimine thiazolidine furan carboxamide compound shown in a formula (I) in preparing β -glucuronidase inhibitor,

in the formula (I), R is a substituent group, and the substituent group comprises chlorine, bromine, fluorine, nitro, methyl, methoxy and hydrogen.

2. The method of claim 1, wherein R is 2-Cl, 3-Cl, 4-Cl, 2-F, 4-F, 2,4-Di-F, 2-NO₂、4-NO₂、4-Br、4-Me、4-MeO、H。

3. Use according to claim 1, characterized in that the cyanoimine thiazolidine furoylamide compound has an IC for β -glucuronidase inhibition₅₀The value ranges from 1.2. mu.M to 23.1. mu.M.

4. Use according to claim 1, characterized in that said β -glucuronidase is derived from escherichia coli.

5. The use according to claim 1, wherein the inhibitor is a medicament for the treatment of drug induced diarrhea associated with irinotecan or a non-steroidal anti-inflammatory drug.

(I) technical field

The invention relates to application of a cyanoimine thiazolidine furoylamide compound, in particular to new application of the cyanoimine thiazolidine furoylamide compound in preparation of β -glucuronidase inhibitor, which is beneficial to research and development of a drug for treating drug-induced diarrhea caused by irinotecan or non-steroidal anti-inflammatory drugs and belongs to the technical field of chemical medicine.

(II) background of the invention

Irinotecan (CPT-11), a commonly used drug for treating colon cancer, is metabolized into inactive SN-38 glucuronide (SN-38G) in the liver after entering the human body, and then the SN-38G is excreted into the intestinal tract through the bile duct, hydrolyzed into SN-38 by the enteric bacteria β -glucuronidase, and causes severe delayed diarrhea and intestinal injury after the SN-38 accumulates in the intestinal tract, which seriously affects the progress of chemotherapy.

β -glucuronidase is a member of the glycosidase family 2 and is capable of hydrolyzing β -D-linked glucuronidase linkages, β -glucuronidase can be produced by many microorganisms in the human and animal intestines, and in 2010, researchers have demonstrated for the first time that inhibiting enterobacteria β -glucosidase can alleviate drug-induced diarrhea caused by CPT-11, and have subsequently received extensive attention with respect to the development and application of enterobacteria β -glucuronidase inhibitors.

The cyanoimine thiazolidine furoylamide compound is a derivative containing a 5-phenyl-2-furan structure. The furan ring is rich in electronic groups and can easily form intermolecular hydrogen bonds with a plurality of biological macromolecules, so that the compound containing the 5-phenyl-2-furan structure has various biological activities, such as antibiosis, antitumor, anti-inflammation, insect resistance and the like. The compounds listed in the invention are fully provided by professor tretinoin university of south China agriculture, but no research has been published on whether the compounds have EcGUS inhibitory activity.

Disclosure of the invention

The invention provides application of a cyanoimine thiazolidine furancarboxamide compound in preparation of β -glucuronidase inhibitor, which is beneficial to research and development of drugs for treating drug-induced diarrhea caused by irinotecan or non-steroidal anti-inflammatory drugs.

The technical scheme adopted by the invention is as follows:

the invention provides an application of a cyanoimine thiazolidine furan carboxamide compound shown in a formula (I) in preparation of β -glucuronidase (EcGUS) inhibitor,

in the formula (I), R is a substituent group, and the substituent group comprises chlorine, bromine, fluorine, nitro, methyl, methoxy and hydrogen.

Further, R is 2-Cl, 3-Cl, 4-Cl, 2-F, 4-F, 2,4-Di-F, 2-NO₂、4-NO₂、4-Br、4-Me、4-MeO、H。

Further, the cyanoimine thiazolidine furoylamide compound has IC for β -glucuronidase inhibition₅₀The value ranges from 1.2. mu.M to 23.1. mu.M.

Further, β -glucuronidase is derived from enteric bacteria, preferably Escherichia coli, β -glucuronidase is commercially available from biochemicals such as Sigma Aldrich (Shanghai) trade company, and can be prepared from Escherichia coli.

Further, the inhibitor is a drug for treating drug-induced diarrhea caused by irinotecan or a non-steroidal anti-inflammatory drug.

Compared with the prior art, the invention has the following beneficial effects:

the cyanoimine thiazolidine furoylamide compound is reported to have the EcGUS inhibitory activity for the first time, and the inhibitory activity is very obvious, IC₅₀The values ranged from 1.2. mu.M to 23.1. mu.M (much less than the positive control-IC for D-glucarate-1, 4-lactone₅₀The value is 67.3 mu M), has wide application prospect in the research and development of medicaments for treating drug-induced diarrhea caused by irinotecan or non-steroidal anti-inflammatory drugs.

(IV) description of the drawings

FIG. 1 is a graph showing the inhibitory activity of cyanoimine thiazolidine furoylamides and D-glucaric acid-1, 4-lactone (final concentration: 10. mu.M) against EcGUS.

FIG. 2 is a graph showing the concentration-dependent inhibition curves of cyanoimido thiazolidine furoylamides and D-glucaric acid-1, 4-lactone against EcGUS.

FIG. 3 is a graph showing the type of EcGUS inhibition by compounds 1(A), 2(B) and 3 (C).

(V) detailed description of the preferred embodiments

The invention is described in further detail below with reference to the drawings and specific examples, which are provided for illustration only and are not intended to limit the scope of the invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.