Clioquinol (Iodochlorhydroxyquin) is a neurotoxic antibiotic, an antifungal drug and antiprotozoal agent that is effective against Alzheimer's disease/AD and can induce cancer cell death.
Physicochemical Properties
| Molecular Formula | C9H5NOCLI |
| Molecular Weight | 305.4991 |
| Exact Mass | 304.91 |
| Elemental Analysis | C, 35.38; H, 1.65; Cl, 11.60; I, 41.54; N, 4.58; O, 5.24 |
| CAS # | 130-26-7 |
| Related CAS # | 130-26-7;16524-58-6 (sulfate); |
| PubChem CID | 2788 |
| Appearance | Light yellow to brown solid powder |
| Density | 2.0±0.1 g/cm3 |
| Boiling Point | 350.4±37.0 °C at 760 mmHg |
| Melting Point | 175-183 °C |
| Flash Point | 165.7±26.5 °C |
| Vapour Pressure | 0.0±0.8 mmHg at 25°C |
| Index of Refraction | 1.768 |
| LogP | 3.86 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 2 |
| Rotatable Bond Count | 0 |
| Heavy Atom Count | 13 |
| Complexity | 193 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | ClC1=C(C=CC=N2)C2=C(O)C(I)=C1 |
| InChi Key | QCDFBFJGMNKBDO-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C9H5ClINO/c10-6-4-7(11)9(13)8-5(6)2-1-3-12-8/h1-4,13H |
| Chemical Name | 5-chloro-7-iodoquinolin-8-ol |
| Synonyms | EnteroVioform, Clioquinol, Chinoform, Vioform, Iodochlorhydroxyquin, Entero Septol |
| HS Tariff Code | 2934.99.03.00 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | U251 and MV-4-11 cells are resistant to the anticancer effects of ciprofloxacin (0.01-1000 uM; 72 hours). |
| Cell Assay |
Cell Line: The MV-4-11, and U-251 cell lines Concentration: 0.01, 0.1, 1, 10, 100, 1000 uM Incubation Time: 72 hours Result: In U251 and MV-4-11 cells, the IC50s were 32 and 46 μM, respectively. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Topical absorption is rapid and extensive, especially when the skin is covered with an occlusive dressing or if the medication is applied to extensive or eroded areas of the skin. Clioquinol is absorbed through the skin in sufficient amounts to affect thyroid function tests. Clioquinol is absorbed systemically following topical application to the skin. In 2 studies in which clioquinol combined with a corticosteroid was applied topically to the skin as a cream or ointment, it was estimated that about 2-3% of the dose was absorbed systemically. However, in another study in which the drug was applied alone to the skin as a 3% cream and covered with an occlusive wrap for 12 hr, it was estimated that about 40% of the dose was absorbed percutaneously during this period. Patients with widespread dermatitis were treated with 15-20 g of 3% clioquinol ointment to 40% of the body area twice daily. The serum concentration increased to 0.8-1.2 ug/ml within 4 hr of application. In one patient, 15-20 mg was excreted in the urine daily mainly in the form of conjugated metabolites. This skin treatment resulted in a urinary excretion somewhat less than is obtained after a daily oral dose of 25 mg (one tablet) of clioquinol. Thus, 3-4% of the applied clioquinol was absorbed. 25% was excreted in the urine. Metabolism / Metabolites Clioquinol has known human metabolites that include Clioquinol O-glucuronide. Biological Half-Life 11-14 hr |
| References |
[1]. Clioquinol down-regulates mutant huntingtin expression in\nvitro and mitigates pathology in a Huntington's disease mouse model.\nProc Natl Acad Sci U S A. 2005 Aug 16;102(33):11840-5. [2].Clioquinol induces pro-death autophagy in leukemia and\nmyeloma cells by disrupting the mTOR signaling pathway. Sci Rep. 2014\nJul 18;4:5749. [3].Clioquinol increases the expression of VGF, a neuropeptide\nprecursor, through induction of c-Fos expression. J Pharmacol Sci.\n2014;124(4):427-32. [4].Clioquinol promotes the degradation of metal-dependent\namyloid-\u03b2 (A\u03b2) oligomers to restore endocytosis and ameliorate A\u03b2\ntoxicity. Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4013-8 |
| Additional Infomation |
Iodochlorohydroxyquinoline is a cream-colored to brownish-yellow powder. Practically odorless. Decomposes at 178-179 °C. Used as a topical anti-infective. 5-chloro-7-iodoquinolin-8-ol is a monohydroxyquinoline that is quinolin-8-ol in which the hydrogens at positions 5 and 7 are replaced by chlorine and iodine, respectively. It has antibacterial and atifungal properties, and is used in creams for the treatment of skin infections. It has also been investigated as a chelator of copper and zinc ions for the possible treatment of Alzheimer's disease. It has a role as an antifungal agent, an antineoplastic agent, an antimicrobial agent, an antibacterial agent, a chelator, an antiprotozoal drug and a copper chelator. It is an organochlorine compound, an organoiodine compound and a monohydroxyquinoline. Clioquinol was withdrawn in 1983 due to neurotoxicity. Clioquinol is a Standardized Chemical Allergen. The physiologic effect of clioquinol is by means of Increased Histamine Release, and Cell-mediated Immunity. Clioquinol is an orally bioavailable, lipophilic, copper-binding, halogenated 8-hydroxyquinoline with antifungal, antiparasitic and potential antitumor activities. Clioquinol forms a stable chelate with copper (copper (II) ions), which inhibits the chymotrypsin-like activity of the proteasome; consequently, ubiquitinated proteins may accumulate in tumor cells, followed by tumor cell apoptosis and the inhibition of tumor angiogenesis. In addition, the clioquinol-copper complex appears to decrease the expression of androgen receptors (AR) in human copper-enriched prostate cancer cells. Serum levels of copper are often elevated in patients with cancer; copper chelation may inhibit copper-dependent endothelial cell proliferation and tumor secretion of angiogenic factors. A potentially neurotoxic 8-hydroxyquinoline derivative long used as a topical anti-infective, intestinal antiamebic, and vaginal trichomonacide. The oral preparation has been shown to cause subacute myelo-optic neuropathy and has been banned worldwide. See also: Iodochlorhydroxyquin (annotation moved to). Drug Indication Used as a topical antifungal treatment. Mechanism of Action Clioquinol is bacteriostatic, however, the precise mechanism of its action is unknown. Therapeutic Uses Amebicides; Anti-Infective Agents, Local Clioquinol is used topically in the treatment of tinea pedis, tinea cruris, and other skin infections caused by dermatophytic fungi (ringworm). MEDICATION (VET): has been used as an intestinal anti-infective. Topical anti-infective; anti-amebic For more Therapeutic Uses (Complete) data for CLIOQUINOL (7 total), please visit the HSDB record page. Drug Warnings Although clioquinol previously was used in the treatment of diaper rash (diaper dermatitis), use of the drug in children currently is not recommended, and use in those younger than 2 years of age is contraindicated. Clioquinol generally appears to be well tolerated following topical application to the skin. Local irritation, rash, and sensitivity reactions have been reported occasionally. If any of these effects occurs, the drug should be discontinued and a physician consulted. Cross sensitivity with other hydroxyquinoline and quinoline derivatives (eg, certain antimalarials) and, occasionally, to iodides can occur. Clioquinol can stain the skin, and discoloration of the hair and nails has been reported rarely. Prolonged use of the drug can result in overgrowth of nonsusceptible organisms, which may require appropriate therapy. When clioquinol is used topically in fixed combination with hydrocortisone, the usual precautions associated with topical corticosteroid therapy should be observed. Because of an association between oculotoxic/neurotoxic effects (eg, optic neuritis, optic atrophy, subacute myelo-optic neuropathy) and oral clioquinol therapy (usually at high dosages for prolonged periods) and the availability of effective alternative topical antifungals, use of clioquinol in children is not recommended, and use in those younger than 2 years of age is contraindicated. Percutaneously absorbed clioquinol, which contains iodine, may interfere with certain thyroid function tests (eg, protein-bound iodine); therefore, the manufacturer recommends that at least 1 month elapse between discontinuance of topical therapy with the drug and performance of these tests. Clioquinol also may produce false positive results in the ferric chloride test for phenylketonuria when the drug is present in urine or the diaper. For more Drug Warnings (Complete) data for CLIOQUINOL (8 total), please visit the HSDB record page. Pharmacodynamics Clioquinol is a broad-spectrum antibacterial with antifungal properties. Application of clioquinol to extensive or eroded areas of the skin may lead to increased protein-bound iodine (PBI) levels within 1 week. In addition, elevated PBI levels may occur when relatively small areas of the skin are treated with clioquinol for more than 1 week. |
Solubility Data
| Solubility (In Vitro) | DMSO : 50~61 mg/mL (163.67~199.67 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (6.81 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: 2.08 mg/mL (6.81 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2733 mL | 16.3666 mL | 32.7332 mL | |
| 5 mM | 0.6547 mL | 3.2733 mL | 6.5466 mL | |
| 10 mM | 0.3273 mL | 1.6367 mL | 3.2733 mL |