500-92-5

• 常用中文名：氯胍
• 常用英文名：Proguanil
• CAS号：500-92-5
• 分子式：C₁₁H₁₆ClN₅
• 分子量：253.73100
• 相关类别： 原料药 抗寄生虫病药 抗疟药
• 发布时间：2018-03-22 08:00:00
• 更新时间：2024-01-03 14:01:39
• Proguanil是一种抗疟药前体药物,代谢为活性代谢物环鸟苷。环鸟苷是一种二氢叶酸还原酶(DHFR)抑制剂。

名称

• 中文名: 氯苯胍
• 英文名: proguanil
• 中文别名: 氯胍; 氯胍; N-(4-氯苯基)-N'-(异丙基)-双胍
• 英文别名: bigumal; chloroguanide; N-(4-CHLOROPHENYL)-N'-(ISOPROPYL)-IMIDODICARBONIMIDIC DIAMIDE; EINECS 207-915-6; Chlorguanide-D6Cl; PROGUANIL; chlorguanide; paludrine; ChlorguanideCl

物化性质

• 密度: 1.29g/cm3
• 沸点: 402.7ºC at 760mmHg
• 熔点: 129°
• 分子式: C₁₁H₁₆ClN₅
• 分子量: 253.73100
• 闪点: 197.4ºC
• 精确质量: 253.10900
• PSA: 83.79000
• LogP: 3.26330
• 折射率: 1.6110 (estimate)
• 储存条件: 2-8℃
• 分子结构:

  1、 摩尔折射率：67.91

  2、 摩尔体积（cm³/mol）：196.4

  3、 等张比容（90.2K）：511.6

  4、 表面张力（dyne/cm）：45.9

  5、 极化率（10-24cm3）：26.92

生物活性

• 描述: Proguanil是一种抗疟药前体药物,代谢为活性代谢物环鸟苷。环鸟苷是一种二氢叶酸还原酶(DHFR)抑制剂。
• 相关类别:
  信号通路 >> 抗感染 >> 寄生物
  研究领域 >> 感染
• 体外研究: Proguanil本身在体外仅具有弱的抗疟活性(IC50 =2.4-19μM),其有效性取决于活性代谢物cycloguanil(IC50 = 0.5-2.5nM)。环胍是二氢叶酸还原酶(DHFR)抑制剂。 atovaquone和氯胍的组合在体外是协同的。两种药物对疟疾寄生虫的配子体细胞和红细胞前期(肝)阶段都有活性[1]。 Proguanil作为双胍而不是其代谢产物cycloguanil(寄生虫二氢叶酸还原酶[DHFR]抑制剂),以增强atovaquone效果;由于其他线粒体电子转运抑制剂(如粘噻唑和抗霉素)的作用不会因含有氯胍而改变,因此氯胍介导的增强对atovaquone具有特异性[2]。氯胍,代谢产物4-氯苯基-1-双胍(CPB)和活性代谢产物环胍(CG)可逆地抑制5-HT3受体反应,IC50分别为1.81,1.48和4.36μM[3]。
• 体内研究: Proguanil可诱导大鼠不育,这可能通过扭曲Sertoli细胞形成的血-睾丸屏障起作用。持续时间依赖性显着降低身体和器官重量以及精子参数。氯胍治疗大鼠的血清睾酮水平显着降低[4]。给予Malarone(atovaquone和氯胍)以实验性地研究B. gibsoni感染慢性期的两只狗和三只处于急性期的狗导致寄生虫血症减少,并且观察到临床改善[5]。
• 细胞实验: 培养从16至18日龄大鼠获得的支持细胞，并用0.3μM至10μM的氯胍治疗5天，之后测定支持细胞活力和细胞核完整性。此外，评估转铁蛋白和胶质细胞源性神经营养因子的遗传表达[4]。
• 动物实验: 大鼠：每天给10至12周大鼠组施用氯胍（2.9mg / kg体重），分别为5天和6周。此后，取体重和生殖器官重量，分析精子参数，同时进行睾丸和附睾的组织学检查。此外，确定血清睾酮，促黄体激素和促卵泡激素水平[4]。
• 参考文献:

  [1]. Pudney M, et al. Atovaquone and proguanil hydrochloride: a review of nonclinical studies. J Travel Med. 1999 May;6 Suppl 1:S8-12.

  [2]. Srivastava IK, et al. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999 Jun;43(6):1334-9.

  [3]. Lochner M, et al. The antimalarial drug proguanil is an antagonist at 5-HT3 receptors. J Pharmacol Exp Ther. 2014 Dec;351(3):674-84.

  [4]. Stephen AO, et al. Prolonged administration of proguanil induces reproductive toxicity in male rats. J Toxicol Sci. 2011 Oct;36(5):587-99.

  [5]. Iguchi A, et al. The in vitro interactions and in vivo efficacy of atovaquone and proguanil against Babesia gibsoni infection in dogs. Vet Parasitol. 2013 Nov 8;197(3-4):527-33.

毒性和生态

CHEMICAL IDENTIFICATION RTECS NUMBER : DU1225000 CHEMICAL NAME : Biguanide, 1-(p-chlorophenyl)-5-isopropyl- CAS REGISTRY NUMBER : 500-92-5 BEILSTEIN REFERENCE NO. : 2811599 LAST UPDATED : 199612 DATA ITEMS CITED : 14 MOLECULAR FORMULA : C11-H16-Cl-N5 MOLECULAR WEIGHT : 253.77 WISWESSER LINE NOTATION : GR DMYUM&MYUM&MY1&1 HEALTH HAZARD DATA ACUTE TOXICITY DATA TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 15 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : 14XBAV "International Congress of Chemotherapy, Proceedings of the 3rd Congress, 1963," Kuemmerle, H.P., and Prezios, P., Stuttgart, Fed. Rep. Ger., Georg Thieme Verlag, 1964 Volume(issue)/page/year: -,367,1964 TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 40 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CLDND* Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 50 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CLDND* Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 25 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CLDND* Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 22 mg/kg TOXIC EFFECTS : Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - other esterases REFERENCE : BJPCAL British Journal of Pharmacology and Chemotherapy. (London, UK) V.1-33, 1946-68. For publisher information, see BJPCBM. Volume(issue)/page/year: 4,14,1949 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rabbit DOSE/DURATION : 150 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CLDND* Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - rabbit DOSE/DURATION : 50 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CLDND* Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Bird - chicken DOSE/DURATION : 400 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CLDND* Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Bird - chicken DOSE/DURATION : 60 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CLDND* Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) ** OTHER MULTIPLE DOSE TOXICITY DATA ** TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 250 mg/kg/5D-I TOXIC EFFECTS : Related to Chronic Data - death REFERENCE : BJPCAL British Journal of Pharmacology and Chemotherapy. (London, UK) V.1-33, 1946-68. For publisher information, see BJPCBM. Volume(issue)/page/year: 5,438,1950 ** REPRODUCTIVE DATA ** TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 700 mg/kg SEX/DURATION : female 7 day(s) pre-mating TOXIC EFFECTS : Reproductive - Fertility - female fertility index (e.g. # females pregnant per # sperm positive females; # females pregnant per # females mated) REFERENCE : MEXPAG Medicina Experimentalis. (Basel, Switzerland) V.1-11, 1959-64; V.18-19, 1968-69. For publisher information, see JNMDBO. Volume(issue)/page/year: 10,361,1964 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 70 mg/kg SEX/DURATION : female 7 day(s) pre-mating TOXIC EFFECTS : Reproductive - Fertility - female fertility index (e.g. # females pregnant per # sperm positive females; # females pregnant per # females mated) REFERENCE : TXAPA9 Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- Volume(issue)/page/year: 13,228,1968 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 504 mg/kg SEX/DURATION : female 42 day(s) pre-mating TOXIC EFFECTS : Reproductive - Maternal Effects - ovaries, fallopian tubes REFERENCE : MEXPAG Medicina Experimentalis. (Basel, Switzerland) V.1-11, 1959-64; V.18-19, 1968-69. For publisher information, see JNMDBO. Volume(issue)/page/year: 10,361,1964 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 252 mg/kg SEX/DURATION : female 21 day(s) pre-mating TOXIC EFFECTS : Reproductive - Maternal Effects - uterus, cervix, vagina REFERENCE : MEXPAG Medicina Experimentalis. (Basel, Switzerland) V.1-11, 1959-64; V.18-19, 1968-69. For publisher information, see JNMDBO. Volume(issue)/page/year: 10,361,1964

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制备

由硫氯酸钠与水合肼加成、重排，最后经甲醛在乙醇中缩合而制得。