Ingredients8-Hydroxyquinoline, also known as oxine, is an organic compound derived from the heterocycle quinoline. Its molecular formula is C₉H₇NO, with CAS number 148-24-3. It is characterized by a planar double aromatic ring system consisting of a phenol fused with a pyridine. The position of the donor atoms gives the molecule strong metal-chelating properties, making it an ideal ligand for forming stable complexes with various metal ions. Its chemical structure includes a quinoline ring with an OH group attached to the eighth carbon atom.
Hydroxyquinoline is classified as a heterocyclic compound because it is a cyclic compound whose rings contain atoms different from carbon; notably, there is a nitrogen atom within one of the rings. A colorless solid, its conjugate base is a chelating agent used for the quantitative determination of metal ions. 8-Hydroxyquinoline is freely soluble in ethanol, acetone, chloroform, and benzene but is insoluble in water.
The term "hydroxyquinoline" as used in dietary supplement and natural-product contexts most commonly refers specifically to the 8-isomer (8-HQ; sometimes labeled "8-quinolinol" or "oxyquinoline"). Other positional isomers exist (2-hydroxyquinoline, 7-hydroxyquinoline, etc.), but their pharmacological profiles differ substantially and they are addressed separately in the chemical literature. The sulfate salt form is commonly designated oxyquinoline sulfate or hydroxyquinoline sulfate and is the principal form found in over-the-counter topical products.
8-Hydroxyquinoline is an alkaloid that occurs in plants of the families Asteraceae and Euphorbiaceae. It is a natural product found in the root exudate of the invasive plant Centaurea diffusa. Centaurea diffusa (a variety of knapweed) is a naturally occurring plant from the Balkans which has become a prolific weed in many parts of the world, especially in the United States.
The ecological role of 8-HQ in C. diffusa has been studied in the context of plant allelopathy, though its precise function remains debated. Using nutrient manipulation treatments in hydroponic culture, researchers found that the exudation of 8-HQ by C. diffusa was very limited and transient; it was further shown that C. diffusa utilizes 8-HQ for its own acquisition of iron, a nutrient deficient in many of its alkaline, invaded habitats. The question of its phytotoxic allelopathic function in real field conditions remains unresolved: contrary to a literature report, 8-hydroxyquinoline was not detected in root exudates of in vitro grown C. diffusa nor could it be identified in the root extract; however, a report from a different group maintains that 8-hydroxyquinoline can be released from roots of C. diffusa following a diurnal rhythm.
8-Hydroxyquinoline is encountered in several distinct chemical and commercial forms relevant to health applications:
8-Hydroxyquinoline has had an excellent reputation as a topical anti-infective for many years and is listed as the active ingredient in liquid bandages such as New Skin®. The 19th edition of the United States Dispensatory, published in 1907, described it as "a very powerful and well-regarded antiseptic." This early 20th-century documentation represents one of the earliest formalized references to the compound's medical utility in Western pharmacopeia literature.
The halogenated derivative clioquinol (also known historically as iodochlorhydroxyquin) was developed as a pharmaceutical agent derived from the 8-HQ scaffold. Clioquinol was widely used as an oral antibiotic before being taken off the market in many countries in 1970, after it was linked to subacute myelo-optic neuropathy (SMON) in Japan, leading to vision loss with many patients left wheelchair-bound. Clioquinol was previously indicated for intestinal amebiasis until the 1970s; this severe side effect was only observed in Japan and has been disputed.
The parent quinoline scaffold, from which 8-hydroxyquinoline is derived, has a broader ethnobotanical history. Angustureine was first isolated in 1999 from Galipea officinalis, which has been used in traditional herbal medicine to treat fever, dyspepsia, dysentery, and chronic diarrhea. This plant is a source of 2-substituted tetrahydroquinoline alkaloids, structurally related to 8-hydroxyquinoline. The direct ethnobotanical use of 8-HQ itself in pre-modern traditional medicine is not documented in the peer-reviewed literature reviewed here; its medicinal history is primarily one of pharmaceutical and industrial chemistry rather than classical botanical traditions.
8-Hydroxyquinoline (8-HQ) is a small planar molecule with a lipophilic effect and a metal chelating ability. It plays a significant role in chemical synthesis, and it has become clear that 8-hydroxyquinoline derivatives are incredibly adaptable molecules with a wide range of uses in industrial and medical chemistry.
The defining structural feature enabling most biological activity is the combination of the phenolic hydroxyl group at position 8 and the pyridine nitrogen atom, which together act as a bidentate chelator. In aqueous solution, 8-hydroxyquinoline has a pKa value of approximately 9.9; it reacts with metal ions, losing the proton and forming 8-hydroxyquinolinato-chelate complexes.
8-Hydroxyquinolines (8HQs) are small planar molecules with an ability to form complexes with divalent metal ions. Some of the biological properties of 8HQs arise from their ability to chelate metals; for example, metal chelation of 8HQs is useful for anticancer applications and the treatment of neurodegenerative diseases such as Alzheimer's or Parkinson's disease. In these uses, the chelation of metals leads to reduced production of reactive oxygen species (ROS), thereby avoiding oxidative stress and cellular damage.
The chelation chemistry is central to virtually all of 8-HQ's biological activities. 8-Hydroxyquinoline (8-hq) exhibits potent antimicrobial activity against Staphylococcus aureus bacteria with MIC = 16.0–32.0 µM owing to its ability to chelate metal ions such as Mn²⁺, Zn²⁺, and Cu²⁺ to disrupt metal homeostasis in bacterial cells.
Given its chelating ability, 8-HQ can facilitate metal transport inside cells. It can also influence key biological processes such as the generation of reactive oxygen species (ROS), that may induce oxidative stress in cancer cells; by binding to DNA and interfering with replication and transcription; or by inhibiting critical enzymes for cancer cells.
In the intracellular environment, Cu(II) complexes can be reduced by cellular reductants such as glutathione (GSH); the formed Cu(I) complex can be re-oxidized producing reactive oxygen species (ROS), or as Cu(I) has high affinity for GSH, the release of the original ligand is also possible.
PBT2 works, similar to clioquinol, as a copper–zinc ionophore that redistributes copper and zinc inside the cell. In turn, this induces phosphorylation of glycogen synthase kinase 3 α- and β-isoforms, which lowers Aβ levels. Ionophore activity — facilitating the transport of metal ions across cell membranes — is now understood as a distinct and potentially more therapeutically relevant mechanism compared to simple chelation-mediated metal depletion.
On the basis of inhibition by chelation of Mn²⁺ and Mg²⁺, explanations have been proposed for why 8-hydroxyquinoline inhibits synthesis of ribosomal and polydisperse RNA more than that of 5S RNA and tRNA, and for why protein synthesis is not immediately inhibited in the intact yeast cell. This mechanism helps explain 8-HQ's selective antifungal properties.
Clioquinol damaged the cell wall and inhibited the formation of pseudohyphae by C. albicans. The 8-hydroxy-5-quinolinesulfonic acid derivatives compromised the functional integrity of cytoplasmic membranes.
8-HQ is a potent antioxidant whose effects depend not only on the formation of coordination complexes with iron ions, but also on scavenging activities due to the redox properties of the 8-hydroxyl group. No pro-oxidant effects were observed in a set of standard assays.
8-HQs have antimicrobial activity against a spectrum of bacterial pathogens including methicillin-resistant Staphylococcus aureus, Streptococcus mutans, and Streptococcus sobrinus.
In terms of mechanism against Mycobacterium tuberculosis, researchers demonstrated that the 8-hydroxyquinoline series has rapid bactericidal activity against M. tuberculosis; the activity of the 8-HQ series is potentiated by copper ions and is dependent on copper, since activity was reduced when copper was depleted from the medium; exposure to 8-HQs led to an increase in intracellular copper, with no changes seen for other metal cations (zinc, iron, magnesium, manganese, or calcium).
A structure-activity relationship study of the 8-hydroxyquinoline series — a privileged scaffold with anticancer, antifungal, and antibacterial activities — conducted using 26 analogs found that 8-hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC₉₀) of <5 µM for some analogs; small substitutions at C5 resulted in the most potent activity.
Evidence strength: All current antibacterial evidence is from in vitro and preclinical studies. No human clinical trials examining 8-hydroxyquinoline as a stand-alone oral or systemic antibacterial agent have been identified in peer-reviewed literature for contemporary indications.
The 8-hydroxyquinoline core is a privileged scaffold for drug design; research has aimed at clarifying the antifungal mechanism of action of clioquinol, 8-hydroxy-5-quinolinesulfonic acid, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid. The antifungal mode of action of these derivatives on Candida spp. and dermatophytes was investigated using sorbitol protection assay, cellular leakage effect, ergosterol binding assay, and scanning electron microscopy.
Iron chelation is considered a key mechanism for antifungal action: it is known that ciclopirox, one of the most potent and broad-spectrum antifungal agents, kills fungal cells by chelating Fe³⁺, subtracting iron ions from the fungal cells; ciclopirox is also known to be the only antifungal agent which, due to its mechanism of action, does not induce resistances in fungal strains. The 8-HQ scaffold operates through a similar iron-chelation principle in many derivatives.
Evidence strength: Antifungal evidence for 8-HQ and its derivatives is predominantly in vitro (cell culture and animal model data). The sulfate salt form is approved under US OTC regulations for topical antifungal indications, reflecting a limited but formally recognized evidence base for topical use.
The 1:3 complex formed between Fe(III) and 8-hq [Fe(8-hq)₃] can readily transport Fe(III) across the bacterial cell membrane and deliver iron into the bacterial cell, harnessing a dual antimicrobial mechanism of action that combines the bactericidal activity of iron with the metal chelating effect of 8-hq to kill bacteria. The antimicrobial potency of Fe(8-hq)₃ is significantly enhanced in comparison with 8-hq alone. Resistance development by S. aureus toward Fe(8-hq)₃ is considerably delayed compared with ciprofloxacin and 8-hq. This represents preclinical (in vitro) research only.
The connection between 8-HQ derivatives and Alzheimer's disease (AD) stems from the metal dyshomeostasis hypothesis of neurodegeneration. Biochemical indicators of AD include β-amyloid (Aβ) plaques, neurofibrillary tangles caused by hyperphosphorylated tau protein, oxidative stress, metal dyshomeostasis, low levels of acetylcholine, and neuroinflammation. Considering the multifactorial nature of AD, there has been an increase in research for novel multitarget compounds; the 8-hydroxyquinoline moiety is a privileged metal-binding agent with Aβ antiaggregating properties.
Clioquinol not only prevents or reverses extracellular Aβ aggregation, but also transports metal ions as membrane-penetrating metal complexes to increase intracellular metal concentration, thereby initiating protective cell signaling events to degrade Aβ and prevent toxicity. In a pilot Phase II clinical trial, CQ was well tolerated and attenuated the rate of cognitive decline in AD patients; however, further development was halted due to a contaminant during the manufacturing process. A small Phase II, placebo-controlled trial of clioquinol in 36 AD patients failed to show clinical improvement in cognition, and one patient developed impaired visual acuity and color vision likely due to the medication.
PBT2 was the subject of three Phase II clinical trials for Alzheimer's disease ('EURO', 'IMAGINE', and 'IMAGINE EXTENSION') and one for Huntington's disease ('REACH2HD'). The cognition efficacy results for Alzheimer's disease were mixed.
A study of PBT2 indicated that it was well tolerated in mild AD patients and appeared to benefit two tests of executive function, although not a larger outcome measure of cognition.
HQs, including clioquinol, can inhibit Aβ aggregation, including in metal-free conditions. Despite the positive outcome in vitro and in vivo, human clinical trials of PBT2 failed to give the anticipated results, and there is no evidence that PBT2 is of benefit in AD patients.
Evidence strength: Clinical trials with 8-HQ derivatives in AD have been Phase II, small in scale, and have produced mixed or negative results for primary cognitive endpoints. There is currently no approved 8-HQ-based treatment for Alzheimer's disease, and the evidence base is insufficient to establish clinical efficacy.
In a 6-month, Phase II double-blind randomized controlled trial in 109 HD patients, PBT2 was found to be safe and well tolerated with minimal serious adverse events. PBT2 was generally safe and well tolerated in patients; however, the potential benefit on executive function will need to be confirmed in a larger study.
Evidence strength: Phase II data suggest acceptable short-term tolerability of PBT2 in HD patients, but no Phase III confirmatory trials have been completed, and clinical efficacy has not been established.
8-Hydroxyquinoline (8HQ) is a small planar molecule with a lipophilic effect and a metal chelating ability. As a result, 8HQ and its derivatives hold medicinal properties such as antineurodegenerative, anticancer, antioxidant, antimicrobial, anti-inflammatory, and antidiabetic activities.
Copper/iron binding and transportation into cells are prerequisites for its cancer cell growth-inhibitory activities. More recently, 8-HQ use has been proposed in combination with current cancer drugs such as paclitaxel. Because 8-HQ is a cancer stem cell active compound, the combination with paclitaxel produces a better therapeutic effect compared to either 8-HQ or paclitaxel alone in MCF7 and MDA-MB-435 xenograft models.
The antiproliferative activity of 8-HQ hydrazone copper(II) complexes was evaluated in malignant melanoma (A-375) and lung (A-549) cancer cells. The complexes showed higher activity than the corresponding free ligand, and most complexes were more active than cisplatin. Compounds selected for additional studies induced reactive oxygen species and double-strand breaks in both cancer cell types; the most promising compound presented low IC₅₀ values, and high induction of oxidative stress and DNA damage, which eventually led to high rates of apoptosis.
Antiproliferative/cytotoxic properties of 8-HQ derivatives on HeLa cells in the presence of transition metal ions (Cu²⁺, Fe³⁺, Co²⁺, Ni²⁺) have been reported; the ligands were tested for their cytotoxicity on HeLa cancer cells, both in the absence and in the presence of copper. The symmetric L14 compound exhibited the highest differential activity between the ligand alone (IC₅₀ = 23.7 µM) and its copper complex (IC₅₀ = 1.8 µM).
Evidence strength: All anticancer evidence for 8-HQ and its metal complexes is preclinical — exclusively in vitro cell culture and animal xenograft models. Little information on human safety of 8-HQ as an anticancer agent is available. No completed human clinical trials for 8-HQ as an anticancer treatment have been identified in the sources reviewed.
Due to the COVID-19 pandemic, antiviral activities of 8-HQ derivatives attracted considerable interest. A few publications have dealt with the antiviral activities of 8-HQ and its derivatives; novel 8-hydroxyquinoline derivatives were synthesized and investigated for their activity against dengue virus.
The antiviral activities of two novel quinoline derivatives were evaluated in vitro against the dengue virus serotype 2 (DENV2); both exhibited significant inhibitory activities against this virus.
Evidence strength: Antiviral evidence is limited to in vitro studies. No human clinical data exist establishing antiviral efficacy of 8-HQ or its derivatives against any virus.
Numerous biological activities, such as antibacterial, antineoplastic, antidiabetic, and antiviral qualities, are displayed by 8-HQ and its derivatives. Quinoline has undergone significant modification since the 1980s, yielding derivatives with notable biological activities, such as antibacterial, antioxidant, and antidiabetic characteristics.
Evidence strength: Antidiabetic claims for 8-HQ and its derivatives are based solely on in vitro and in silico studies. No clinical trial data are available.
It was recently demonstrated that 8-hydroxyquinoline (8-HQ) showed significant leishmanicidal effects in vitro and in vivo, and research has aimed to develop a topical formulation containing 8-HQ to assess its activity in experimental cutaneous leishmaniasis. 8-HQ was formulated at 1% and 2% concentrations, showing suitable emulsion properties and membrane permeability. The prepared creams showed no toxic events in the skin of treated mice; 8-HQ creams were able to reduce the size of the lesion and tissue parasitism in experimental cutaneous leishmaniasis.
Evidence strength: Preliminary animal model data only; no human clinical trial data are available for this indication.
A historical reference in the 8-HQ scientific literature notes research on anticalculus and antiplaque activity of 8-hydroxyquinoline sulfate dating to 1976 (Depalma et al., J. Dent. Res. 1976), indicating early interest in its application to oral biofilm control through its metal-chelating and antimicrobial properties. The current evidence base for this application is not documented in recent systematic reviews or clinical trials.
As a result of its metal chelation and lipophilic properties, 8-HQ and its derivatives have demonstrated activity relevant to antineurodegenerative, anticancer, antioxidant, antimicrobial, anti-inflammatory, and antidiabetic applications. Metal ions play an important role in biological processes and in metal homeostasis; metal imbalance is the leading cause of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The primary body systems implicated in the scientific literature are:
The following dosage information is derived directly from the sources identified and should not be extrapolated or generalized:
The most significant safety event associated with 8-HQ derivatives is the SMON epidemic linked to oral clioquinol. Clioquinol was widely used as an oral antibiotic before being taken off the market in many countries in 1970, after it was linked to subacute myelo-optic neuropathy (SMON) in Japan, leading to vision loss with many patients left wheelchair-bound. The common pathology of CQ-associated SMON was reproduced in animals but none of the proposed modes of toxicity explained the restriction of CQ-induced SMON to Japan. Given the re-emergence of CQ and related analogues as neuroprotectants, it is crucial to understand the underlying mechanism of CQ-induced toxicity.
A small molecule screen to find drugs that induce mitochondrial dysfunction in vitro identified clioquinol and the structurally related 8-hydroxyquinoline (8-OHQ). Their mitochondrial liability, pro-oxidative, and cytotoxic activity was subsequently confirmed in some cell lines but not in others.
While 8-hydroxyquinoline is normally not toxic, chelated forms of 8-hydroxyquinoline do have cytotoxic effects in mammalian cells. This cytotoxic effect is empirically observed for both the charged and uncharged reaction products. The context-dependent toxicity of 8-HQ — benign as the free molecule but potentially cytotoxic when complexed with endogenous metals — is a key consideration in any pharmaceutical or supplemental context.
Little information on human safety of 8-HQ as a potential therapeutic agent is available. The research literature has focused predominantly on in vitro and animal models, with Phase II clinical trials limited to PBT2 (a second-generation derivative), not the parent 8-HQ molecule itself.
In the Phase II placebo-controlled trial of clioquinol in AD patients, one patient developed impaired visual acuity and color vision likely due to the medication. This is consistent with the historical SMON-related visual toxicity observed with oral clioquinol use.
The sulfate salt form has a documented record of topical use. According to 21 CFR 310.545, oxyquinoline sulfate is used in OTC astringent drug products, and oxyquinoline is used in topical OTC antifungal drug products. Formulation guidance from the USDA for veterinary preparations notes that it is not to be applied on deep skin wounds or punctures; it is not meant for internal use.
Given the re-emergence of CQ and related analogues as neuroprotectants, it is crucial to understand the underlying mechanism of CQ-induced toxicity. A small molecule screen to find drugs that induce mitochondrial dysfunction in vitro identified both clioquinol and the structurally related 8-OHQ. This structural alert has implications for the safety profiling of all 8-HQ-scaffold compounds intended for systemic use.
Although 8-hydroxyquinoline (8HQ) and its derivatives have gained considerable scientific interest over the years, there remains a notable lack of an integrated review that comprehensively addresses their synthetic strategies, structural diversity, and broad pharmacological potential. Despite the advances in derivatizing 8HQ, many studies focus narrowly on either synthetic methods or isolated biological effects, lacking an integrated view that links chemical design to therapeutic potential. The substantial majority of reported biological activities — antimicrobial, anticancer, antineurodegenerative, antidiabetic, antiviral — are supported by in vitro or animal model data only. Phase II human clinical trial data exist exclusively for the second-generation derivative PBT2 in Alzheimer's disease and Huntington's disease, with mixed and inconclusive efficacy outcomes.
Health conditions that Hydroxyquinoline may help support.
Body systems that Hydroxyquinoline may help support.
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