5-氯-2-甲基-4-异噻唑啉-3-酮 | 26172-55-4

• 物质功能分类: 化学农药原药 - 杀菌剂 - 其他杀菌剂
• 分子结构分类: 有机化合物 - 有机卤素化合物 - 芳基卤化物
• 中文名称: 5-氯-2-甲基-4-异噻唑啉-3-酮
• 中文别名: 甲基氯异塞唑晽酮；5-氯-2-甲基异噻唑啉-3-酮；2-甲基-4-异噻唑啉酮；异噻唑啉酮；卡松IXE；甲基氯异噻唑啉酮；卡松；5-氯-2-甲基-异噻唑啉-3-酮；5-氯-2-甲基-2H-异噻唑-3-酮；5-氯-2-甲基-异噻唑酮-3；5-氯-2-甲基-3(2H)异噻唑酮、2-甲基3(2H)异噻唑酮混合物；CIT；CMIT；异噻唑啉酮衍生物；三氯均二苯；氯甲基异噻唑啉酮
• 英文名称: 5-chloro-2-methyl-2H-isothiazol-3-one
• 英文别名: 5-chloro-2-methyl-4-isothiazolin-3-one；chloromethylisothiazolinone；CMIT；5-chloro-2-methyl-1,2-thiazol-3-one
• CAS: 26172-55-4
• 化学式: C₄H₄ClNOS
• mdl: MFCD00792550
• 分子量: 149.601
• InChiKey: DHNRXBZYEKSXIM-UHFFFAOYSA-N

物化性质

• 熔点：
  42-45?C
• 沸点：
  109.7°C
• 密度：
  1.25 (14% aq.)
• 溶解度：
  可溶于氯仿（轻微）、DMSO（轻微）、甲醇（轻微、加热）
• LogP：
  0.240 (est)
• 颜色/状态：
  Crystals from ligroin (60-90 °C)
• 蒸汽压力：
  0.018 mm Hg at 25 °C
• 分解：
  When heated to decomposition it emits toxic vapors of NOx, SOx, and Cl-
• 解离常数：
  Does not dissociate into ions
• 保留指数：
  1226
• 稳定性/保质期：
  1. 异噻唑啉酮通过断开细菌和藻类蛋白质的键而起杀生作用。当它与微生物接触后，会迅速且不可逆地抑制其生长，导致微生物细胞死亡，因此对常见细菌、真菌、藻类等具有很强的抑制和杀灭效果。该物质杀菌效率高，降解性好，无残留，操作安全，配伍性和稳定性强，使用成本低，并能与氯及大多数阴离子、阳离子及非离子表面活性剂相溶。在高剂量下，异噻唑啉酮对生物黏泥剥离有显著效果。

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  8
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  45.6
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

毒理性

• 毒性总结

识别和使用：5-氯-2-甲基-4-异噻唑啉-3-酮（CMI）形成晶体。它被用作化妆品、卫生产品、油漆、乳液、切削油、纸张涂料以及储水和冷却装置中的抗菌防腐剂。CMI还用于液压破碎流体。它在美国注册为杀虫剂，但批准的杀虫剂用途可能会定期更改，因此必须咨询联邦、州和地方当局以获取当前批准的用途。CMI通常与2-甲基-4-异噻唑啉-3-酮（MI）结合使用。人类暴露和毒性：Kathon CG，一种含有5-氯-2-甲基-4-异噻唑啉-3-酮和2-甲基-4-异噻唑啉-3-酮作为活性成分的化妆品防腐剂，似乎是欧洲接触性皮炎的常见原因。动物研究：将5-氯-2-甲基-4-异噻唑啉-3-酮和2-甲基-4-异噻唑啉-3-酮（CMI/MIT）的混合物稀释在玉米油中，通过灌胃给予雄性和雌性大鼠，剂量为每天0、0.26、0.78、2.33和7.0毫克/千克体重。在最高CMI/MIT暴露下，观察到雄性血清甘油三酯水平降低和雌性肝相位1外源代谢酶的诱导，伴有肝脏的细微组织学变化。CMI/MIT的混合物在缺乏大鼠肝脏代谢系统的细菌（菌株TA 100）和培养的哺乳动物细胞中产生了点突变。在存在大鼠肝脏代谢系统的情况下，需要高10倍的浓度才能在培养的哺乳动物细胞中诱导点突变。在使用代谢系统和S. typhimurium的情况下没有观察到致突变活性。在果蝇的性连锁隐性致死试验、小鼠的体内细胞遗传学试验、培养的大鼠肝细胞的不定期DNA合成试验和体外细胞转化试验中得到了阴性结果。在免疫毒性研究中，CMI（与蛋白质结合）诱导了耳廓淋巴节点细胞增殖反应，而MI（与蛋白质结合不良）在类似于CMI的浓度下既没有刺激增殖反应也没有诱导淋巴节点大小的增加。

IDENTIFICATION AND USE: 5-chloro-2-methyl-4-isothiazolin-3-one (CMI) forms crystals. It is used as antimicrobial preservative in cosmetics, hygiene products, paints, emulsions, cutting oils, paper coatings, and water storage and cooling units. CMI is also used in hydraulic fracturing fluids. It is registered for pesticide use in the USA but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses. CMI is often used in a combination products with 2-methyl-4-isothiazolin-3-one (MI). HUMAN EXPOSURE AND TOXICITY: Kathon CG, a cosmetics preservative containing, as active ingredients, 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, appears to be a frequent cause of contact dermatitis in Europe. ANIMAL STUDIES: A mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (CMI/MIT) diluted in corn oil was administered by gavage to male and female rats at 0, 0.26, 0.78, 2.33 and 7.0 mg/kg body weight per day. Reduction of serum triglyceride levels in males and induction of hepatic phase 1 xenobiotic metabolizing enzymes in females accompanied by subtle histological changes in the liver were observed at the highest CMIT/MIT exposure. A mixture of CMI/MIT produced point mutations in the absence of a rat-liver metabolizing system in bacteria (strain TA 100) and mammalian cells in culture. In the presence of rat-liver metabolizing system a 10-fold higher concentration was required to induce point mutations in mammalian cells in culture. No mutagenic activity was observed with the metabolizing system and S. typhimurium. Negative results were obtained in the sex-linked recessive lethal assay in Drosophila, the in vivo cytogenetic assay in mice, the unscheduled DNA synthesis assay in cultured rat hepatocytes, and the in vitro cell transformation assay. In immunotoxicity studies CMI, which binds to protein, induced an auricular lymph node cell proliferation response while MI, which poorly binds to protein, neither stimulated a proliferative response nor induced an increase in lymph node size at concentrations similar to CMI.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 副作用

皮肤致敏剂 - 一种可以诱导皮肤产生过敏反应的制剂。

Skin Sensitizer - An agent that can induce an allergic reaction in the skin.

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 相互作用

此前我们报道，将HL60细胞短暂暴露于5-氯-2-甲基-4-异噻唑啉-3-酮（CMI）和2-甲基-4-异噻唑啉-3-酮（MI）的混合物中，会使细胞进入氧化应激状态，从而诱导凋亡和坏死。在本研究中，流式细胞术分析显示CMI/MI诱导了钙稳态的早期扰动，增加了细胞质和线粒体钙，并耗尽了内质网（ER）的内存储备。钙螯合剂BAPTA-AM减少了由CMI/MI致死剂量引起的坏死和继发性坏死，以及坏死剂量引起的DeltaPsim损失和S-谷胱甘肽化，但并未对抗CMI/MI诱导的凋亡、线粒体钙摄取和线粒体超极化。这表明增加的细胞质钙并不是凋亡诱导的原因，而内质网和线粒体之间的交叉对话可能是凋亡诱导的原因。GSH-OEt预处理增加了细胞GSH含量，降低了S-谷胱甘肽化和细胞质及线粒体钙水平，从而保护细胞免受凋亡和坏死转变的影响。因此，GSH的耗竭程度，与蛋白质S-谷胱甘肽化水平相平行，可能在增加钙水平上具有因果关系。线粒体钙的增加可能是凋亡的原因，而坏死与细胞质钙过载有关。这些发现表明，特定蛋白质的S-谷胱甘肽化作用作为钙和氧化还原信号之间的分子连接器。

Previously we reported that brief exposure of HL60 cells to a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one (CMI) and 2-methyl-4-isothiazolin-3-one (MI) shifts the cells into a state of oxidative stress that induces apoptosis and necrosis. In this study, flow cytometric analysis showed that CMI/MI induces early perturbation of calcium homeostasis, increasing cytosolic and mitochondrial calcium and depleting the intracellular endoplasmic reticulum (ER) stores. The calcium chelator BAPTA-AM reduced necrosis and secondary necrosis, the loss of DeltaPsim and S-glutathionylation induced by necrotic doses of CMI/MI, but did not protect against CMI/MI-induced apoptosis, mitochondrial calcium uptake and mitochondrial hyperpolarization. This indicates that increased cytoplasmic calcium does not have a causal role in the induction of apoptosis, while cross-talk between the ER and mitochondria could be responsible for the induction of apoptosis. GSH-OEt pretreatment, which enhances cellular GSH content, reduced S-glutathionylation and cytosolic and mitochondrial calcium levels, thus protecting against both apoptosis and necrosis shifting to apoptosis. Therefore, the degree of GSH depletion, paralleled by the levels of protein S-glutathionylation, may have a causal role in increasing calcium levels. The mitochondrial calcium increase could be responsible for apoptosis, while necrosis is associated with cytoplasmic calcium overload. These findings suggest that S-glutathionylation of specific proteins acts as a molecular linker between calcium and redox signalling.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下），以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  8
• 危险品标志：
  C
• 安全说明：
  S24,S26,S28,S36/37/39,S45,S60,S61
• 危险类别码：
  R20/21/22,R34,R50,R43
• WGK Germany：
  1
• 危险品运输编号：
  UN 1760 8/PG 2
• RTECS号：
  NX8156850
• 海关编码：
  2934999090
• 包装等级：
  III
• 危险类别：
  8
• 储存条件：
  库房应保持低温、通风和干燥。

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: 5-Chloro-2-methyl-4-isothiazolin-3-one, tech grade, ¿14% in water. CMI/MI ¿2.0
Synonyms: CMI

---

Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

---

Section 3. Composition/information on ingredients.
Ingredient name: 5-Chloro-2-methyl-4-isothiazolin-3-one, tech grade, ¿14% in water. CMI/MI ¿2.0
CAS number: 26172-55-4

---

Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

---

Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

---

Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels, refrigerated.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

---

Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C4H4ClNOS
Molecular weight: 149.6

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides, hydrogen chloride, sulfur oxides.

---

Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

---

Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

---

Section 14. Transportation information
Non-harzardous for air and ground transportation.

---

Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

---

SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

异噻唑啉酮：性能优异的水处理剂

异噻唑啉酮是一种性能优异的水处理剂，具有良好的混溶性，能与氯、缓蚀剂、阻垢分散剂、大多数阴离子、阳离子及非离子表面活性剂相混溶。市面上流通的商品通常是5-氯-2-甲基-4-异噻唑啉-3-酮（CMI）和2-甲基-4-异噻唑啉-3-酮（MI）的混合物，同时会加入金属亚硝酸盐或金属硝酸盐以提高稳定性防止分解。

异噻唑啉酮的作用机制是通过断开细菌和藻类蛋白质的键而起杀生作用。与微生物接触后，它能迅速地不可逆地抑制其生长，从而导致微生物细胞的死亡。这种水处理剂对常见细菌（如硫酸盐还原菌、淤泥成型菌）、真菌（如铁氧化菌、霉菌、酵母菌）和藻类等具有很强的抑制和杀灭作用。异噻唑啉酮具有以下特点：杀生效率高，降解性好，无残留，操作安全，配伍性好，稳定性强，使用成本低。在高剂量时，它还能对生物粘泥剥离产生显著效果。

目前，这种水处理剂已经被广泛应用于钢铁冶炼、油田注水、火力发电、造纸、炼油、化工、轻纺、工业清洗、农药、切削油水性涂料、日化、油墨、染料、制革等领域。

用途

1. 用于处理工业循环水：起杀菌灭藻作用，是一种广普的杀菌防腐剂，能有效杀灭藻类、细菌和真菌。该活性单剂可广泛应用于工业冷却水、油田回罐水、造纸行业、管道、涂料、油漆、橡胶以及化妆品、感光胶片及洗涤用品等工业。
2. 用于高血压治疗：血管紧张素转化酶抑制剂，前体药物。
3. 杀菌剂：广泛用于工业水处理、游泳池水处理等领域。

类别

• 有毒物质

可燃性危险特性

• 可燃，在燃烧时会分解产生有毒氯化物、硫氧化物和氮氧化物气体。

储运特性

• 库房低温通风，干燥保存。

灭火剂

• 水
• 二氧化碳
• 干粉
• 砂土

反应信息

• 作为反应物：
  描述：

  5-氯-2-甲基-4-异噻唑啉-3-酮 在 三氯氧磷 、 氨 作用下， 以 乙腈 为溶剂， 以61%的产率得到5-chloro-N-methylisothiazol-3-amine
  参考文献：
  名称：

  异噻唑类。第14部分：新的3-氨基取代的异噻唑二氧化物及其单和二卤代衍生物

  摘要：

  由二硫代丙酰胺开始合成在C-4和C-5未取代的3-烷基氨基-和3-芳基氨基异噻唑二氧化物。利用环化过程中的直接氯化或在最终的3-氨基异噻唑二氧化物衍生物上用溴进行加成-消除过程，相应的5-氯-，4,5-二氯-或4-溴异噻唑也可能是提供。

  DOI：

  10.1016/j.tet.2003.09.064
• 作为产物：
  描述：

  1,2-二氯乙烷 在 磺酰氯 作用下， 生成 5-氯-2-甲基-4-异噻唑啉-3-酮
  参考文献：
  名称：

  3-Isothiazolones as biocides

  摘要：

  本文披露了一些新颖的化合物，最适当地被称为3-异噻唑酮。这些化合物和含有它们的组合物表现出广泛的生物杀灭性能，并且特别有效用于控制微生物。

  公开号：

  US04105431A1

文献信息

• Kinetic studies on the reactions of 3-isothiazolones with 2-methyl-2-propanethiol
  作者：John O. Morley、A. Jayne Oliver Kapur、Michael H. Charlton

  DOI：10.1002/kin.20235

  日期：2007.5

  The kinetics of the ring-opening reactions of the 3-isothiazolones (1a–d) with aqueous 2-methyl-2-propanethiol has been explored at pH 4. The results strongly suggest that the reaction is second order in thiol and third order overall. Extrapolation of the kinetic data gives third-order rate constants that lie in the order (1a) > (1b) > (1c) > (1d) in line with the known biological activity of these

  3-异噻唑酮 (1a-d) 与 2-甲基-2-丙硫醇水溶液的开环反应动力学已在 pH 4 下进行了探索。结果强烈表明该反应在硫醇中是二级反应，总体上是三级反应. 动力学数据的外推给出了三阶速率常数，其顺序为 (1a) > (1b) > (1c) > (1d)，与这些衍生物的已知生物活性一致。该反应的机理被认为涉及异噻唑酮的硫原子上的一个硫醇的攻击，伴随着第二个硫醇与酰胺氮的氢键合。RHF 6-31G** 水平的异噻唑酮的结构和电子特性的计算是支持性的。© 2007 Wiley Periodicals, Inc. Int J Chem Kinet 39: 254–260, 2005
• 一种3-异噻唑啉酮化合物的管道式连续化生产方法
  申请人：大连百傲化学股份有限公司

  公开号：CN110483438A

  公开（公告）日：2019-11-22

  本发明公开了一种3‑异噻唑啉酮类化合物的管道式连续化生产方法，通过管道反应器系统将硫代酰胺类化合物、催化剂、溶剂和氯气进行混合反应，反应完成后经后处理得到3‑异噻唑啉酮化合物。本发明解决了3‑异噻唑啉酮化合物现有间歇式生产带来的设备多占地大、产能小、效率低、能耗高、安全系数小的弊端，提供了一种连续化生产3‑异噻唑啉酮化合物的方式，从而使反应过程容易操控、减低了能耗、提高了生产效率及生产过程的安全系数，该工艺是一种是高效节能的安全生产工艺。
• 一种3-异噻唑啉酮类化合物的制备方法
  申请人：大连百傲化学股份有限公司

  公开号：CN112110871A

  公开（公告）日：2020-12-22

  本发明公开了一种3‑异噻唑啉酮类化合物的制备方法，包括以下步骤：在反应体系中加入原料与溶剂，搅拌混合；在混合后的溶液中加入脱水剂，搅拌反应；向反应体系中通入氯气，反应混合物搅拌反应，过滤分离得到产物。本发明通过在反应体系中加入化学脱水剂，与反应体系中的水或醇发生反应，从而脱除体系中的水或醇，以避免由水或醇导致的副反应，提高反应的收率，经济效益显著。
• Antimicrobial 5-substituted-3-isothiazolone compounds and methods of use
  申请人：Rohm and Haas

  公开号：EP1223171A1

  公开（公告）日：2002-07-17

  Novel antimicrobial compounds based on 5-substituted 3-isothiazolones, having Formula I: where the 5-substituent is an aryl or heterocyclic ether/thioether group, are disclosed. These 5-substituted 3-isothiazolones provide enhanced antimicrobial activity over that of related 3-isothiazolones, particularly when the 5-substituent is a substituted pyridinyl thioether group.

  本发明揭示了基于5-取代的3-异噻唑酮的新型抗微生物化合物，其具有以下化学式I：其中5-取代基是芳基或杂环醚/硫醚基。这些5-取代的3-异噻唑酮比相关的3-异噻唑酮具有更强的抗微生物活性，特别是当5-取代基为取代的吡啶硫醚基时。
• Antimicrobial compounds and methods of use
  申请人：——

  公开号：US20030065192A1

  公开（公告）日：2003-04-03

  Novel antimicrobial compounds based on 5-substituted 3-isothiazolones, where the 5-substituent is an aryl or heterocyclic ether/thioether group, are disclosed. These 5-substituted 3-isothiazolones provide enhanced antimicrobial activity over that of related 3-isothiazolones, particularly when the 5-substituent is a substituted pyridinyl thioether group.

  本发明揭示了基于5-取代的3-异噻唑酮的新型抗微生物化合物，其中5-取代基是芳基或杂环醚/硫醚基团。这些5-取代的3-异噻唑酮具有比相关的3-异噻唑酮更强的抗微生物活性，特别是当5-取代基是取代的吡啶硫醚基团时。