Combined system capable of enhancing antibacterial effect of indane compounds
阅读说明：本技术 一种能增强茚满类化合物抗菌效果的组合体系 (Combined system capable of enhancing antibacterial effect of indane compounds ) 是由 向飞 于 2018-12-20 设计创作，主要内容包括：本发明提供了一种由第一苯并咪唑类化合物与第二苯并咪唑类化合物所构成的组合体系,所述组合体系能与现有技术中已知的特定茚满类化合物产生协同的抑菌作用。(The invention provides a combination system consisting of a first benzimidazole compound and a second benzimidazole compound, wherein the combination system can generate a synergistic bacteriostatic action with a specific indane compound known in the prior art.)
1. The composition system comprises a first benzimidazole compound and a second benzimidazole compound which are different from each other and have a molar ratio of 0.01-100, wherein the first benzimidazole compound and the second benzimidazole compound are selected from one of compounds 1-8 shown as follows:
2. combination system according to claim 1, characterized in that the combination system is one selected from the group consisting of:
the compound 2 and the compound 4 form a combined system with a molar ratio of 50,
the compound 3 and the compound 7 form a combined system with a molar ratio of 50,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 4 and the compound 8 form a combined system with a molar ratio of 25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 6 form a combined system with a molar ratio of 100,
the compound 2 and the compound 7 form a combined system with a molar ratio of 50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 25,
the compound 4 and the compound 8 form a combined system with a molar ratio of 50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 6 form a combined system with a molar ratio of 100,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 50,
the compound 4 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 3 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 2 form a combined system with a molar ratio of 50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 100,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 4 form a combined system with a molar ratio of 1,
the compound 1 and the compound 3 form a combined system with a molar ratio of 1,
the compound 5 and the compound 8 form a combined system with a molar ratio of 50,
the compound 5 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 6 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 4 and the compound 7 form a combined system with a molar ratio of 100,
the compound 3 and the compound 4 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 6 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 4 form a combined system with a molar ratio of 100,
the compound 5 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 4 and the compound 8 form a combined system with a molar ratio of 1,
the compound 2 and the compound 6 form a combined system with a molar ratio of 1,
the compound 3 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 6 and the compound 8 form a combined system with the molar ratio of 1,
the compound 3 and the compound 7 form a combined system with a molar ratio of 0.25,
a combination system formed by the compound 1 and the compound 4 in a molar ratio of 25,
the compound 2 and the compound 3 are combined at a molar ratio of 0.01,
the compound 4 and the compound 5 form a combined system with a molar ratio of 75,
the compound 1 and the compound 2 form a combined system with a molar ratio of 75,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 8 form a combined system with a molar ratio of 100,
the compound 2 and the compound 5 form a combined system with a molar ratio of 75,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 8 form a combined system with a molar ratio of 50,
the compound 2 and the compound 6 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 6 form a combined system with a molar ratio of 0.75,
the compound 2 and the compound 4 form a combined system with a molar ratio of 0.25,
the compound 7 and the compound 8 form a combined system with a molar ratio of 0.50,
a combination system formed by the compound 1 and the compound 2 in a molar ratio of 25,
the compound 1 and the compound 5 form a combined system with a molar ratio of 100,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.01,
the compound 3 and the compound 8 form a combined system with a molar ratio of 100,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 8 form a combined system with a molar ratio of 75,
a combination system formed by the compound 2 and the compound 3 in a molar ratio of 25,
the compound 6 and the compound 7 form a combined system with the molar ratio of 1,
a combination system formed by the compound 3 and the compound 4 in a molar ratio of 25,
the compound 1 and the compound 4 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.01,
the compound 7 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 4 and the compound 6 are combined into a combined system with a molar ratio of 0.01,
the compound 7 and the compound 8 form a combined system with a molar ratio of 75,
the compound 2 and the compound 8 form a combined system with the molar ratio of 1,
the compound 2 and the compound 7 form a combined system with a molar ratio of 100,
the compound 1 and the compound 4 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 4 form a combined system with a molar ratio of 0.75,
the compound 7 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 6 form a combined system with a molar ratio of 0.75,
the compound 4 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.75,
a combination system formed by the compound 1 and the compound 5 in a molar ratio of 25,
the compound 5 and the compound 8 form a combined system with the molar ratio of 1,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.75,
the compound 3 and the compound 6 form a combined system with a molar ratio of 75,
the compound 5 and the compound 6 form a combined system with a molar ratio of 0.50,
the compound 5 and the compound 7 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 4 form a combined system with a molar ratio of 75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 75,
the compound 3 and the compound 6 form a combined system with a molar ratio of 50,
the compound 6 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 2 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 4 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 7 form a combined system with a molar ratio of 100,
the compound 1 and the compound 3 are combined at a molar ratio of 100,
a combination system formed by the compound 4 and the compound 6 in a molar ratio of 25,
the compound 2 and the compound 5 form a combined system with a molar ratio of 25,
a combination system formed by the compound 2 and the compound 6 in a molar ratio of 25,
the compound 4 and the compound 6 form a combined system with a molar ratio of 0.25,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 25,
the compound 6 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 50,
the compound 2 and the compound 3 form a combined system with a molar ratio of 50,
the compound 3 and the compound 4 form a combined system with a molar ratio of 1,
the compound 6 and the compound 8 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 3 form a combined system with a molar ratio of 0.75,
the compound 3 and the compound 7 form a combined system with a molar ratio of 1,
the compound 1 and the compound 5 form a combined system with a molar ratio of 0.75,
the compound 7 and the compound 8 form a combined system with a molar ratio of 0.01,
the compound 1 and the compound 4 form a combined system with a molar ratio of 0.25,
the compound 5 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 4 form a combined system with a molar ratio of 0.01,
the combination system of the compound 1 and the compound 6 with a molar ratio of 75,
the compound 6 and the compound 7 form a combined system with a molar ratio of 100,
the compound 6 and the compound 7 form a combined system with a molar ratio of 25,
the compound 5 and the compound 6 form a combined system with a molar ratio of 1,
the compound 4 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 1 and the compound 7 form a combined system with a molar ratio of 75,
the compound 3 and the compound 4 are formed into a combined system with a molar ratio of 0.01,
the compound 4 and the compound 6 form a combined system with a molar ratio of 75,
the compound 3 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 5 and the compound 8 form a combined system with a molar ratio of 0.01,
the compound 1 and the compound 6 form a combined system with a molar ratio of 100,
the compound 4 and the compound 7 form a combined system with a molar ratio of 25,
the compound 1 and the compound 3 form a combined system with a molar ratio of 0.25,
the compound 1 and the compound 4 form a combined system with a molar ratio of 0.01,
a combination system formed by the compound 2 and the compound 7 in a molar ratio of 1.
3. Combination system according to claim 2, characterized in that the combination system is one selected from the group consisting of:
the compound 2 and the compound 4 form a combined system with a molar ratio of 50,
the compound 3 and the compound 7 form a combined system with a molar ratio of 50,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 4 and the compound 8 form a combined system with a molar ratio of 25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 6 form a combined system with a molar ratio of 100,
the compound 2 and the compound 7 form a combined system with a molar ratio of 50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 25,
the compound 4 and the compound 8 form a combined system with a molar ratio of 50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 6 form a combined system with a molar ratio of 100,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 50,
the compound 4 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 3 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 2 form a combined system with a molar ratio of 50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 100,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 4 form a combined system with a molar ratio of 1,
the compound 1 and the compound 3 form a combined system with a molar ratio of 1,
the compound 5 and the compound 8 form a combined system with a molar ratio of 50,
the compound 5 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 6 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 4 and the compound 7 form a combined system with a molar ratio of 100,
the compound 3 and the compound 4 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 6 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 4 form a combined system with a molar ratio of 100,
the compound 5 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 4 and the compound 8 form a combined system with a molar ratio of 1,
the compound 2 and the compound 6 form a combined system with a molar ratio of 1,
the compound 3 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 6 and the compound 8 form a combined system with the molar ratio of 1,
the compound 3 and the compound 7 form a combined system with a molar ratio of 0.25,
a combination system formed by the compound 1 and the compound 4 in a molar ratio of 25,
the compound 2 and the compound 3 are combined at a molar ratio of 0.01,
the compound 4 and the compound 5 form a combined system with a molar ratio of 75,
the compound 1 and the compound 2 form a combined system with a molar ratio of 75,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 8 form a combined system with a molar ratio of 100,
the compound 2 and the compound 5 form a combined system with a molar ratio of 75,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 8 form a combined system with a molar ratio of 50,
the compound 2 and the compound 6 form a combined system with a molar ratio of 0.50,
compound 4 and compound 6 in a molar ratio of 0.75.
4. Combination according to claim 3, characterized in that said combination is one selected from the group consisting of:
the compound 2 and the compound 4 form a combined system with a molar ratio of 50,
the compound 3 and the compound 7 form a combined system with a molar ratio of 50,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 4 and the compound 8 form a combined system with a molar ratio of 25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 6 form a combined system with a molar ratio of 100,
the compound 2 and the compound 7 form a combined system with a molar ratio of 50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 25,
the compound 4 and the compound 8 form a combined system with a molar ratio of 50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 6 form a combined system with a molar ratio of 100,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 50,
the compound 4 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 3 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 2 form a combined system with a molar ratio of 50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 100,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 4 form a combined system with a molar ratio of 1,
the compound 1 and the compound 3 form a combined system with a molar ratio of 1,
the compound 5 and the compound 8 form a combined system with a molar ratio of 50,
the compound 5 and the compound 8 form a combined system with a molar ratio of 0.50,
a combination system of compound 1 and compound 7 at a molar ratio of 0.25.
5. Combination according to claim 4, characterized in that the combination is one selected from the following combinations:
the compound 2 and the compound 4 form a combined system with a molar ratio of 50,
the compound 3 and the compound 7 form a combined system with a molar ratio of 50,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 4 and the compound 8 form a combined system with a molar ratio of 25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 6 form a combined system with a molar ratio of 100,
the compound 2 and the compound 7 form a combined system with a molar ratio of 50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 25,
the compound 4 and the compound 8 form a combined system with a molar ratio of 50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 6 form a combined system with a molar ratio of 100,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 50,
the compound 4 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.75,
a combination system of compound 1 and compound 6 at a molar ratio of 0.25.
6. The composition containing the combination system according to any one of claims 1 to 5, wherein the composition is formulated into an oral preparation in a form selected from the group consisting of tablets, capsules and granules.
7. The composition of claim 6, wherein the oral formulation further comprises a diluent and a lubricant.
8. The composition of claim 7 wherein the diluent is selected from the group consisting of pregelatinized starch, dextrin, sucrose, microcrystalline cellulose, sorbitol, mannitol, lactose, calcium sulfate, calcium hydrogen phosphate and calcium phosphate.
9. The composition of claim 7, wherein the lubricant is one selected from the group consisting of sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, paraffin oil, paraffin wax, glyceryl monostearate, glyceryl monopalmitate, sodium acetate, sodium chloride, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, polyoxyethylene monostearate and polyoxyethylene lauryl ether.
10. The composition of claim 8 or 9, wherein said formulation further comprises a compound having the structure:
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a combination system capable of enhancing the antibacterial effect of indane compounds through synergistic action.
Background
Infectious diseases are a broad class of diseases caused by infection with microorganisms such as bacteria, parasites, fungi, or viruses, and can be transmitted directly or indirectly through various routes. Although various anti-infective agents including antibiotics, antivirals, antifungals, and antiparasitics are currently used to treat infectious diseases, the disease remains one of the leading causes of morbidity or mortality worldwide. In 2010, about 1500 million deaths worldwide are due to infectious diseases.
Although the application of antibiotics such as penicillins, cephalosporins, quinolones and the like and synthetic antibacterial drugs plays a great role in the fight between human beings and bacterial infection, the spread of the bacterial infection is effectively inhibited. However, with the increasing popularity of the use of the above-mentioned antibacterial agents, the problem of bacterial resistance due to improper medication is becoming more and more prominent. There is therefore still a need to develop drugs with highly potent antibacterial activity against partially drug-resistant bacteria.
The patent WO2018172423 discloses a series of indane compounds with antibacterial effects, which exert antibacterial effects by inhibiting LasB, but does not disclose specific antibacterial effects, and the experiments of the inventor find that the antibacterial effects of some compounds disclosed in the patent on common pathogenic bacteria infected by human bodies, such as staphylococcus aureus, are unsatisfactory (not reaching IC 50).
Disclosure of Invention
The invention aims to provide a combination system composed of benzimidazole compounds, which can enhance the bacteriostatic effect of indane compounds through synergistic action.
In order to achieve the above object, one aspect of the present invention provides a combination system composed of a first benzimidazole compound and a second benzimidazole compound, which are different from each other and have a molar ratio of 0.01 to 100, wherein the first benzimidazole compound and the second benzimidazole compound are selected from one of the following compounds:
the benzimidazole compounds of the present invention are all compounds described in the prior art, for example, compounds described in the study of RSC Advance 2015, 56 th.
According to the order of strength of synergistic action in a bacteriostatic test, the combination system disclosed by the invention is preferably one of the following combination systems (CI < 0.5):
the compound 2 and the compound 4 form a combined system with a molar ratio of 50,
the compound 3 and the compound 7 form a combined system with a molar ratio of 50,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 4 and the compound 8 form a combined system with a molar ratio of 25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 6 form a combined system with a molar ratio of 100,
the compound 2 and the compound 7 form a combined system with a molar ratio of 50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 25,
the compound 4 and the compound 8 form a combined system with a molar ratio of 50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 6 form a combined system with a molar ratio of 100,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 50,
the compound 4 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 3 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 2 form a combined system with a molar ratio of 50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 100,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 4 form a combined system with a molar ratio of 1,
the compound 1 and the compound 3 form a combined system with a molar ratio of 1,
the compound 5 and the compound 8 form a combined system with a molar ratio of 50,
the compound 5 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 6 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 4 and the compound 7 form a combined system with a molar ratio of 100,
the compound 3 and the compound 4 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 6 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 4 form a combined system with a molar ratio of 100,
the compound 5 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 4 and the compound 8 form a combined system with a molar ratio of 1,
the compound 2 and the compound 6 form a combined system with a molar ratio of 1,
the compound 3 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 6 and the compound 8 form a combined system with the molar ratio of 1,
the compound 3 and the compound 7 form a combined system with a molar ratio of 0.25,
a combination system formed by the compound 1 and the compound 4 in a molar ratio of 25,
the compound 2 and the compound 3 are combined at a molar ratio of 0.01,
the compound 4 and the compound 5 form a combined system with a molar ratio of 75,
the compound 1 and the compound 2 form a combined system with a molar ratio of 75,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 8 form a combined system with a molar ratio of 100,
the compound 2 and the compound 5 form a combined system with a molar ratio of 75,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 8 form a combined system with a molar ratio of 50,
the compound 2 and the compound 6 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 6 form a combined system with a molar ratio of 0.75,
the compound 2 and the compound 4 form a combined system with a molar ratio of 0.25,
the compound 7 and the compound 8 form a combined system with a molar ratio of 0.50,
a combination system formed by the compound 1 and the compound 2 in a molar ratio of 25,
the compound 1 and the compound 5 form a combined system with a molar ratio of 100,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.01,
the compound 3 and the compound 8 form a combined system with a molar ratio of 100,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 8 form a combined system with a molar ratio of 75,
a combination system formed by the compound 2 and the compound 3 in a molar ratio of 25,
the compound 6 and the compound 7 form a combined system with the molar ratio of 1,
a combination system formed by the compound 3 and the compound 4 in a molar ratio of 25,
the compound 1 and the compound 4 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.01,
the compound 7 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 4 and the compound 6 are combined into a combined system with a molar ratio of 0.01,
the compound 7 and the compound 8 form a combined system with a molar ratio of 75,
the compound 2 and the compound 8 form a combined system with the molar ratio of 1,
the compound 2 and the compound 7 form a combined system with a molar ratio of 100,
the compound 1 and the compound 4 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 4 form a combined system with a molar ratio of 0.75,
the compound 7 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 6 form a combined system with a molar ratio of 0.75,
the compound 4 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.75,
a combination system formed by the compound 1 and the compound 5 in a molar ratio of 25,
the compound 5 and the compound 8 form a combined system with the molar ratio of 1,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.75,
the compound 3 and the compound 6 form a combined system with a molar ratio of 75,
the compound 5 and the compound 6 form a combined system with a molar ratio of 0.50,
the compound 5 and the compound 7 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 4 form a combined system with a molar ratio of 75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 75,
the compound 3 and the compound 6 form a combined system with a molar ratio of 50,
the compound 6 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 2 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 4 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 7 form a combined system with a molar ratio of 100,
the compound 1 and the compound 3 are combined at a molar ratio of 100,
a combination system formed by the compound 4 and the compound 6 in a molar ratio of 25,
the compound 2 and the compound 5 form a combined system with a molar ratio of 25,
a combination system formed by the compound 2 and the compound 6 in a molar ratio of 25,
the compound 4 and the compound 6 form a combined system with a molar ratio of 0.25,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 25,
the compound 6 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 50,
the compound 2 and the compound 3 form a combined system with a molar ratio of 50,
the compound 3 and the compound 4 form a combined system with a molar ratio of 1,
the compound 6 and the compound 8 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 3 form a combined system with a molar ratio of 0.75,
the compound 3 and the compound 7 form a combined system with a molar ratio of 1,
the compound 1 and the compound 5 form a combined system with a molar ratio of 0.75,
the compound 7 and the compound 8 form a combined system with a molar ratio of 0.01,
the compound 1 and the compound 4 form a combined system with a molar ratio of 0.25,
the compound 5 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 4 form a combined system with a molar ratio of 0.01,
the combination system of the compound 1 and the compound 6 with a molar ratio of 75,
the compound 6 and the compound 7 form a combined system with a molar ratio of 100,
the compound 6 and the compound 7 form a combined system with a molar ratio of 25,
the compound 5 and the compound 6 form a combined system with a molar ratio of 1,
the compound 4 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 1 and the compound 7 form a combined system with a molar ratio of 75,
the compound 3 and the compound 4 are formed into a combined system with a molar ratio of 0.01,
the compound 4 and the compound 6 form a combined system with a molar ratio of 75,
the compound 3 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 5 and the compound 8 form a combined system with a molar ratio of 0.01,
the compound 1 and the compound 6 form a combined system with a molar ratio of 100,
the compound 4 and the compound 7 form a combined system with a molar ratio of 25,
the compound 1 and the compound 3 form a combined system with a molar ratio of 0.25,
the compound 1 and the compound 4 form a combined system with a molar ratio of 0.01,
a combination system formed by the compound 2 and the compound 7 in a molar ratio of 1.
More preferably, the combination system according to the present invention is one selected from the following combination systems (CI < 0.2):
the compound 2 and the compound 4 form a combined system with a molar ratio of 50,
the compound 3 and the compound 7 form a combined system with a molar ratio of 50,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 4 and the compound 8 form a combined system with a molar ratio of 25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 6 form a combined system with a molar ratio of 100,
the compound 2 and the compound 7 form a combined system with a molar ratio of 50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 25,
the compound 4 and the compound 8 form a combined system with a molar ratio of 50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 6 form a combined system with a molar ratio of 100,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 50,
the compound 4 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 3 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 2 form a combined system with a molar ratio of 50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 100,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 4 form a combined system with a molar ratio of 1,
the compound 1 and the compound 3 form a combined system with a molar ratio of 1,
the compound 5 and the compound 8 form a combined system with a molar ratio of 50,
the compound 5 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 6 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 4 and the compound 7 form a combined system with a molar ratio of 100,
the compound 3 and the compound 4 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 6 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 4 form a combined system with a molar ratio of 100,
the compound 5 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 4 and the compound 8 form a combined system with a molar ratio of 1,
the compound 2 and the compound 6 form a combined system with a molar ratio of 1,
the compound 3 and the compound 8 form a combined system with a molar ratio of 0.50,
the compound 6 and the compound 8 form a combined system with the molar ratio of 1,
the compound 3 and the compound 7 form a combined system with a molar ratio of 0.25,
a combination system formed by the compound 1 and the compound 4 in a molar ratio of 25,
the compound 2 and the compound 3 are combined at a molar ratio of 0.01,
the compound 4 and the compound 5 form a combined system with a molar ratio of 75,
the compound 1 and the compound 2 form a combined system with a molar ratio of 75,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 8 form a combined system with a molar ratio of 100,
the compound 2 and the compound 5 form a combined system with a molar ratio of 75,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.50,
the compound 3 and the compound 8 form a combined system with a molar ratio of 50,
the compound 2 and the compound 6 form a combined system with a molar ratio of 0.50,
compound 4 and compound 6 in a molar ratio of 0.75.
Further preferably, the combination system according to the present invention is one selected from the following combination systems (CI < 0.1):
the compound 2 and the compound 4 form a combined system with a molar ratio of 50,
the compound 3 and the compound 7 form a combined system with a molar ratio of 50,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 4 and the compound 8 form a combined system with a molar ratio of 25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 6 form a combined system with a molar ratio of 100,
the compound 2 and the compound 7 form a combined system with a molar ratio of 50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 25,
the compound 4 and the compound 8 form a combined system with a molar ratio of 50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 6 form a combined system with a molar ratio of 100,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 50,
the compound 4 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.75,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.25,
the compound 2 and the compound 3 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 2 form a combined system with a molar ratio of 50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 0.25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 100,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.50,
the compound 2 and the compound 4 form a combined system with a molar ratio of 1,
the compound 1 and the compound 3 form a combined system with a molar ratio of 1,
the compound 5 and the compound 8 form a combined system with a molar ratio of 50,
the compound 5 and the compound 8 form a combined system with a molar ratio of 0.50,
a combination system of compound 1 and compound 7 at a molar ratio of 0.25.
Most preferably, the combination system of the present invention is one selected from the following combination systems:
the compound 2 and the compound 4 form a combined system with a molar ratio of 50,
the compound 3 and the compound 7 form a combined system with a molar ratio of 50,
the compound 1 and the compound 6 form a combined system with a molar ratio of 0.01,
the compound 4 and the compound 8 form a combined system with a molar ratio of 25,
the compound 1 and the compound 2 form a combined system with a molar ratio of 0.01,
the compound 2 and the compound 6 form a combined system with a molar ratio of 100,
the compound 2 and the compound 7 form a combined system with a molar ratio of 50,
the compound 3 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 4 and the compound 8 form a combined system with the molar ratio of 0.75,
the compound 3 and the compound 8 form a combined system with a molar ratio of 1,
the compound 1 and the compound 7 form a combined system with a molar ratio of 25,
the compound 4 and the compound 8 form a combined system with a molar ratio of 50,
the compound 6 and the compound 7 form a combined system with a molar ratio of 0.25,
the compound 3 and the compound 6 form a combined system with a molar ratio of 100,
a combination system formed by the compound 1 and the compound 3 in a molar ratio of 50,
the compound 4 and the compound 5 form a combined system with a molar ratio of 0.50,
the compound 1 and the compound 8 form a combined system with a molar ratio of 50,
the compound 1 and the compound 7 form a combined system with a molar ratio of 0.75,
a combination system of compound 1 and compound 6 at a molar ratio of 0.25.
In another aspect of the invention, there is provided a composition comprising a combination system as described above.
Preferably, the composition of the present invention can be prepared into an oral preparation in one dosage form selected from tablets, capsules and granules.
More preferably, the oral formulation further comprises a diluent and a lubricant.
Further preferably, the diluent of the present invention is one selected from pregelatinized starch, dextrin, sucrose, microcrystalline cellulose, sorbitol, mannitol, lactose, calcium sulfate, calcium hydrogen phosphate and calcium phosphate; the lubricant is one selected from sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, paraffin oil, paraffin, glyceryl monostearate, glyceryl monopalmitate, sodium acetate, sodium chloride, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, polyoxyethylene monostearate and polyoxyethylene lauryl ether.
Most preferably, the formulation of the present invention may further comprise a compound having the structure shown below:
the oral solid preparation of the present invention can be prepared by methods known to those skilled in the art, and the methods can be referred to, but not limited to, methods in "pharmacy" (8 th edition) published by the national institute of health and care (Min's republic of China). The preparation method of the granules comprises the step of mixing the combined system, the diluent and the lubricant.
The preparation method of the capsule provided by the invention comprises the steps of mixing the combination system, the diluent and the lubricant, and filling the mixture into capsules. .
The preparation method of the tablet provided by the invention comprises the steps of mixing the combination system, the diluent and the lubricant, and then tabletting to obtain the tablet.
The content of the combination system in the oral solid preparation of the present invention and the dosage to be administered related thereto can be selected and optimized by pharmacological tests well known to those skilled in the art, and the present invention is not particularly limited thereto.
The amount of the adjuvant in the oral solid preparation of the present invention can be selected and optimized by the methods known to those skilled in the art, and the present invention is not limited thereto.
In vitro bacteriostatic test results show that the combination system formed by the first benzimidazole compound and the second benzimidazole compound and the indane compound can generate synergistic bacteriostatic action at a molar ratio of 1: 1.
Detailed Description
The technical solution of the present invention is described in detail and completely with reference to the following embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Test example 1 evaluation of in vitro inhibitory Effect of combination System comprising benzimidazole Compounds on test bacteria
The in-vitro bacteriostatic action of the combined system consisting of the benzimidazole compounds on each tested bacterium is respectively determined by adopting a filter paper sheet method. Specifically, the prepared bacterial suspension (1X 10) was aspirated with a pipette5Per mL, preparation: activating the test strain on TSB culture medium [37 + -1 deg.C for 3 days]And lightly taking a small amount of lawn from the culture medium by using an inoculating loop, respectively adding the lawn into conical flasks containing 50mL of sterile physiological saline), and uniformly coating the lawn on the surface of the cooled agar plate to prepare a bacterium-containing plate. Taking a sterilized filter paper sheet, respectively putting the sterilized filter paper sheet into 6 test substance methanol solutions with concentration gradients which are increased by 2 times, soaking for 1 hour, sticking the soaked 6mm circular filter paper sheet on the prepared bacterium-containing flat plate, sticking 3 filter paper sheets (the filter paper sheets are the same at intervals as far as possible) soaked in the test substance methanol solution with the same molar concentration on each culture dish (the diameter is 90mm), and taking a 50% methanol solution as a blank control. The treated plate containing the bacteria was incubated at 37 ℃ for 24 hours, the diameter of the colony was measured by the cross method, and the Inhibition Ratio (IR) was calculated according to the following formula.
Plotting Inhibition Ratio (IR) on log (c) of total concentration (μ M) of the first benzimidazole compound and the second benzimidazole compound in the combination system, performing linear regression by using Excel, and calculating the total concentration (IC) of the first benzimidazole compound and the second benzimidazole compound in the combination system when specific inhibition effect (fa) is generated according to regression equationfa(A)。
Test example 2 evaluation of in vitro inhibitory Effect of indanes Compounds
In addition, a filter paper sheet method is adopted to evaluate the in-vitro bacteriostatic effect of a part of indane compounds disclosed in WO2018172423 on tested bacteria, and the indane compounds have the structural formula shown as follows:
the ready-prepared bacterial suspension (1X 10) is aspirated by a pipette5Per mL, preparation: activating the test strain on TSB culture medium [37 + -1 deg.C for 3 days]And lightly taking a small amount of lawn from the culture medium by using an inoculating loop, respectively adding the lawn into conical flasks containing 50mL of sterile physiological saline), and uniformly coating the lawn on the surface of the cooled agar plate to prepare a bacterium-containing plate. Taking a sterilized filter paper sheet, respectively putting the sterilized filter paper sheet into 6 test substance methanol solutions with concentration gradients which are increased by 2 times, soaking for 1 hour, sticking the soaked 6mm circular filter paper sheet on the prepared bacterium-containing flat plate, sticking 3 filter paper sheets (the filter paper sheets are the same at intervals as far as possible) soaked in the test substance methanol solution with the same molar concentration on each culture dish (the diameter is 90mm), and taking a 50% methanol solution as a blank control. The treated plate containing the bacteria was incubated at 37 ℃ for 24 hours, the diameter of the colony was measured by the cross method, and the Inhibition Ratio (IR) was calculated according to the following formula.
Plotting Inhibition (IR) against log (c) of the concentration (. mu.M) of said indanes, and linear regression using Excel, and calculating the concentration of said indanes, i.e. IC, at the occurrence of a specific inhibitory effect (fa) from the regression equationfa(A)。
Test example 3 evaluation of synergistic antibacterial action of a benzimidazole compound combination System and indane Compound combination
The tests corresponding to test example 1 and test example 2 were repeated in parallel for each benzimidazole compound combination system and the combination of the indanes.
Mixing a specific benzimidazole compound combination system with the indane compound in a molar ratio of 1:1, and dissolving the mixture in methanol, wherein the molar number of the benzimidazole compound combination system is calculated by the total molar number of the benzimidazole compound in the combination system, and sequentially diluting the mixture into 6 solutions with concentration gradients by 2 times for later use.
The ready-prepared bacterial suspension (1X 10) is aspirated by a pipette5Per mL, preparation: activating the test strain on TSB culture medium [37 + -1 deg.C for 3 days]And lightly taking a small amount of lawn from the culture medium by using an inoculating loop, respectively adding the lawn into conical flasks containing 50mL of sterile physiological saline), and uniformly coating the lawn on the surface of the cooled agar plate to prepare a bacterium-containing plate. Taking a sterilized filter paper sheet, respectively putting the sterilized filter paper sheet into 6 test substance methanol solutions with concentration gradients which are increased by 2 times, soaking for 1 hour, sticking the soaked 6mm circular filter paper sheet on the prepared bacterium-containing flat plate, sticking 3 filter paper sheets (the filter paper sheets are the same at intervals as far as possible) soaked in the test substance methanol solution with the same molar concentration on each culture dish (the diameter is 90mm), and taking a 50% methanol solution as a blank control. The treated plate containing the bacteria was incubated at 37 ℃ for 24 hours, the diameter of the colony was measured by the cross method, and the Inhibition Ratio (IR) was calculated according to the following formula.
The Inhibition Ratio (IR) is used for plotting the log (c) of the total concentration (mu M) of the benzimidazole compounds in the mixed system, Excel is used for linear regression, and the total concentration of the benzimidazole compounds in the mixed system, namely IC (integrated circuit) when the specific inhibition effect (fa) is generated is calculated according to the regression equationfa(mixA)And then, the concentration of the indane compound in the combined system, namely the IC (integrated circuit), during the fa inhibition effect is calculated according to the ratio of the total mole number of the benzimidazole compound in the mixed system to the mole number of the indanefa(mixB)。
Calculating a combination index CI of a combination system consisting of a first benzimidazole compound and a second benzimidazole compound and the indane compound according to the following formula.
When CI <1, synergy was indicated, and smaller CI indicated greater synergy, the results are shown in table 1.
TABLE 1
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