阅读说明：本技术 一类新型靛红类衍生物的制备方法及其潜在抗菌活性 (Preparation method and potential antibacterial activity of novel isatin derivatives ) 是由 朱海亮 苏咪咪 徐镜 杨雨顺 李红林 徐琛 于 2018-06-04 设计创作，主要内容包括：本发明公开了一类新型靛红类生物制备方法及应用,所述的衍生物的结构如式所示：<Image he="488" wi="280" file="DSA0000165050250000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R基团为：<Image he="88" wi="700" file="DSA0000165050250000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image><Image he="325" wi="700" file="DSA0000165050250000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明所述的化合物合成成本较低,分子相对分子质量比其他的抗菌药要小,稳定性强,其结构与沙星类类似,具有潜在的抗菌活性,本发明利用靛红为先导化合物合成具有潜在抗菌效果的化合物,具有潜在的应用前景。(the invention discloses a preparation method and application of novel isatin organisms, wherein the structure of the derivative is shown as , the R group is , the synthesis cost of the compound is low, the relative molecular mass of the molecule is smaller than that of other antibacterial drugs, the stability is strong, the structure is similar to that of sars, and the compound has potential antibacterial activity.)

1. a novel isatin derivative has a structure shown in a formula:

Wherein the R group is:

2. the method for preparing isatin-based derivative according to claim 1, which comprises the steps of:

Step 1, dissolving isatin in DMF, carrying out magnetic stirring to fully dissolve the isatin, adding bromomethylcyclopropane, adding a catalyst potassium carbonate, wherein the mass ratio of the isatin to the bromomethylcyclopropane to the potassium carbonate is 1: 1.2, placing a reaction system at 50 ℃ for refluxing, standing overnight, cooling the reaction to room temperature, transferring the reaction system to a 100mL beaker, adding ice water into the reaction system, stirring while adding the ice water to generate a red solid, washing with ethanol for three times, filtering, and drying to obtain a product in the first step;

Step 2, dissolving benzoic acid with different substituents in ethanol to completely dissolve the benzoic acid, adding concentrated sulfuric acid, refluxing at 95 ℃, detecting the reaction progress by TLC (thin layer chromatography), and then drying the reaction in vacuum to obtain colorless liquid with aromatic odor, which is a second-step product;

Step 3, adding 10mL of 80% hydrazine hydrate into the product obtained in the step 2, reacting at room temperature for 1.5-12 h, detecting the reaction progress by TLC, placing the reaction system in cold hydrazine after the reaction is completed until solid is separated out, filtering, and drying to obtain white solid, namely the product obtained in the third step;

And 4, weighing the product obtained in the step 1, dissolving the product in ethanol, magnetically stirring, heating to completely dissolve the product, adding the product obtained in the step 3, performing ultrasonic treatment, heating to completely dissolve a reactant, adding 200 mu L of acetic acid, reacting at room temperature, detecting the reaction progress by TLC (thin layer chromatography), filtering after the reaction is finished, washing with ethanol for three times to obtain a target product crude product, performing reduced pressure concentration on the crude product solution by using ethanol, and purifying by using silica gel column chromatography to obtain a target product K1-K18.

3. The preparation of novel isatin derivatives according to claims 1 and 2 and their active use in antibacterial drugs.

Technical Field

the invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a novel isatin derivative for selectively inhibiting DNA gyrase and application of the novel isatin derivative in antibacterial drugs.

background

in the past decade, bacterial DNA gyrase has served as an important antibacterial drug targetAs a great deal of attention, DNAGYRASE is a topoisomerase II type which is a heterotetramer A₂B₂the structure, an enzyme that catalyzes DNA double strand breaks and rejoins in bacteria, thereby altering DNA topology, plays an important role in bacterial DNA replication and transcription. Since the discovery of quinolone drugs in 1962, they have been continuously developed as inhibitors of DNA gyrase and are widely used in clinical practice for the treatment of bacterial infectious diseases, and the sarcin drugs are effective antibacterial drugs with the enzyme as a target and have a spectrum property. The structure of the compound designed by the invention is similar to that of a sarcin medicament, so that the compound has potential antibacterial activity.

disclosure of Invention

the invention aims to provide a preparation method of a novel isatin derivative and application of the novel isatin derivative in antibacterial drugs.

the technical scheme is as follows: a novel isatin derivative has the following characteristic structure:

wherein the R group is:

A method for preparing the isatin derivative, which comprises the following steps:

step 1, dissolving isatin in DMF, carrying out magnetic stirring to fully dissolve the isatin, adding bromomethylcyclopropane, adding a catalyst potassium carbonate, wherein the mass ratio of the isatin to the bromomethylcyclopropane to the potassium carbonate is 1: 1.2, placing a reaction system at 50 ℃ for refluxing, standing overnight, cooling the reaction to room temperature, transferring the reaction system to a 100mL beaker, adding ice water into the reaction system, stirring while adding the ice water to generate a red solid, washing with ethanol for three times, filtering, and drying to obtain a product in the first step;

step 2, dissolving benzoic acid with different substituents in ethanol to completely dissolve the benzoic acid, adding concentrated sulfuric acid, refluxing at 95 ℃, detecting the reaction progress by TLC (thin layer chromatography), and then drying the reaction in vacuum to obtain colorless liquid with aromatic odor, which is a second-step product;

Step 3, adding 10mL of 80% hydrazine hydrate into the product obtained in the step 2, reacting at room temperature for 1.5-12 h, detecting the reaction progress by TLC, placing the reaction system in cold hydrazine after the reaction is completed until solid is separated out, filtering, and drying to obtain white solid, namely the product obtained in the third step;

And 4, weighing the product obtained in the step 1, dissolving the product in ethanol, magnetically stirring, heating to completely dissolve the product, adding the product obtained in the step 3, performing ultrasonic treatment, heating to completely dissolve a reactant, adding 200 mu L of acetic acid, reacting at room temperature, detecting the reaction progress by TLC (thin layer chromatography), filtering after the reaction is finished, washing with ethanol for three times to obtain a target product crude product, performing reduced pressure concentration on the crude product solution by using ethanol, and purifying by using silica gel column chromatography to obtain a target product K1-K18.

the invention has the advantages that: the compound has the advantages of low synthesis cost, small molecular relative molecular mass compared with other antibacterial drugs, strong stability and obvious antibacterial application effect, and the target point is DNA gyrase, especially pseudomonas aeruginosa. Experiments prove that the series of compounds have little toxicity to normal cells of human bodies. The invention synthesizes the compound with antibacterial effect by using isatin as a lead compound, and has wide application prospect.

Detailed Description

the present invention is further illustrated in detail by the following examples, but it should be noted that the scope of the present invention is not limited by these examples at all.