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氯胍

氯胍用途

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。

氯胍名称

[ CAS 号 ]:
500-92-5

[ 中文名 ]:
氯苯胍

[ 英文名 ]:
Proguanil

[中文别名 ]:

[英文别名 ]:

bigumal
chloroguanide
EINECS 207-915-6
Chlorguanide-D6Cl
PROGUANIL
chlorguanide
paludrine
ChlorguanideCl

氯胍生物活性

[ 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.

[相关活性小分子]

氯胍物理化学性质

[ 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℃

氯胍毒性和生态

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

氯胍合成路线

详细合成路线

氯胍上下游产品

氯胍上游产品

氯胍下游产品

氯胍制备

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。

氯胍