Combretum quadrangulare

Combretum quadrangulare (Sakae Naa): A Comprehensive Reference

1. Identity, Taxonomy, and Botanical Description

Combretum quadrangulare, commonly known by its Thai name sakae naa (สะแกนา), is a species of flowering plant in the family Combretaceae. It is native to Southeast Asia, particularly the Indo-China region including Cambodia, Laos, Myanmar, Thailand, and Vietnam — known locally as saba in Thai and krang in Khmer. In Vietnamese traditional medicine, the tree is commonly referred to as Tram bau. The species belongs to the family Combretaceae and was formally described by Kurz, hence the full botanical name Combretum quadrangulare Kurz.

The species name quadrangulare refers to its characteristically four-angled twigs. It typically grows 2–10 meters tall, occasionally reaching 12 meters, with young branches featuring four angular sides and wing-like grooves. The leaves are opposite, long-ovate, 3–7.5 cm long and 1.5–4 cm wide, with rounded tips and hairy undersides, while small flowers cluster at leaf axils and branch tips, producing fruits 18–20 mm long with four claw-like wings. The inflorescence is terminal and axillary spikes, with small, yellowish-white flowers. The fruit is dry and thinly four-winged, with seeds that are brownish-red and ellipsoid in shape.

This plant thrives in lowland forests of the wet tropical biome and shows tolerance to saline soils, often harvested from the wild or cultivated ornamentally. It grows in disturbed and secondary forest environments as well as along riverbanks, and is familiar to rural communities throughout its native range.

Common Names and Synonyms

• Thai: Sakae Naa (สะแกนา)
• Vietnamese: Tram Bau
• Khmer: Krang
• Scientific authority: Combretum quadrangulare Kurz (Combretaceae)

Dosage Forms and Common Preparations

Seeds, leaves, and the stem bark are used in Vietnamese traditional medicine; the seeds are administered orally together with ripe bananas as an anthelmintic for ascariasis and oxyuriasis. The dried ripe seeds of sakae naa were ground and dissolved in water before oral administration in anthelmintic applications. Modern ethnobotanical preparations include dried leaf material and concentrated (e.g., 25×) extracts prepared through water and ethanol extraction. In scientific studies, the dried leaves and stems of C. quadrangulare Kurz have been extracted with 50% EtOH and analyzed using HPLC-DAD chromatography. Methanol extracts have also been widely used in preclinical pharmacological investigations.

2. Traditional and Historical Use

Combretum quadrangulare holds significant ethnopharmacological value in Eastern Asian folk medicine, where various parts are used for their alterative, anthelmintic, antipyretic, and astringent properties. The seeds, leaves, as well as the stem bark of the plant are used in Vietnamese and Thai traditional medicine as antihepatitis, antipyretic, antidysenteric, and anthelmintic agents.

The seeds are administered orally together with ripe bananas as an anthelmintic for ascariasis and oxyuriasis. A traditional Thai preparation described in Medicinal Plants in Thailand (Vol. 1, by Promjit Saralamp) specifies grinding 3 g of seeds, mixing them with egg, frying, and taking the preparation once on an empty stomach for threadworm and roundworm infestations in children.

The root of the plant has been used for treatment of abscesses and gonorrhea and as an alterative and anthelmintic. The whole plant has been used for stomachache, treatment of roundworm infestation, and chronic gastrointestinal ailments of children between the ages of 5 and 13 characterized by marked malnutrition, usually associated with intestinal parasitism and abscesses.

Seeds or sometimes other parts of Combretum quadrangulare and related species are widely used as a vermifuge or for other intestinal disorders, while the leaves or roots are employed for poulticing wounds and boils. The leaves are traditionally considered antipyretic and astringent.

In South-East Asia, Combretum is best known as a vermifuge, with seeds or sometimes other parts of C. quadrangulare and related species being widely used as a vermifuge or for other intestinal disorders.

In more recent decades, farmers in regions of Thailand where Mitragyna speciosa (kratom) cultivation and use is restricted have maintained sakae naa cultivation as an alternative, continuing the long-established practice of using its leaves in traditional smoking and chewing contexts. This modern pattern of leaf use is culturally distinct from the older, medically documented anthelmintic and antipyretic traditions recorded in formal ethnobotanical literature.

3. Phytochemistry: Key Constituents and Active Compounds

Most of the isolated compounds from C. quadrangulare belong to the class of triterpenoids and flavonoids; as of the comprehensive literature survey through June 2014, ninety-seven chemical constituents had been isolated from this plant. Subsequent research has continued to add to this count.

Triterpenoids

Previous phytochemical investigations reported the presence of numerous triterpenes, mostly cycloartanes, ursanes, lupanes, and oleananes. Seven novel cycloartane-type triterpenes were isolated from Combretum quadrangulare, and their structures were elucidated on the basis of spectral analysis. Named compounds from the cycloartane class include the quadrangularates (methyl quadrangularate series A through N), quadrangularols, norquadrangularic acids, and, from more recent research, combretanones A–G and combretic acids A and B.

In a screening program for natural products that increase DR5 (death-receptor 5) expression, nine new cycloartane triterpenes — combretanones A–G, combretic acid A, and combretic acid B — were isolated from a MeOH extract of C. quadrangulare leaves, along with known oleanane triterpenes and six known flavonols.

A 2025 study isolated 16 compounds from C. quadrangulare, comprising nine previously undescribed and seven known compounds. Cycloartane-type triterpenoids from C. quadrangulare were found to inhibit PCSK9 secretion; combretic acid A in particular significantly inhibited the synthesis and secretion of PCSK9 and showed higher liver distribution than plasma.

Flavonoids

Former chemical studies on C. quadrangulare reported the presence of over 10 flavonoids from this source. HPLC-DAD analysis of C. quadrangulare extract confirmed the presence of casuarinin, isoorientin A, orientin, ellagic acid, kamatakeni (kumatakenin), and ayanin. Additional flavonoids confirmed in the literature include combretol (an O-methylated flavonol), rhamnocitrin, ombuin, isokaempferide, vitexin, 5-hydroxy-3,7,4′-trimethoxyflavone, and myricetin derivatives. Combretol is an O-methylated flavonol found specifically in C. quadrangulare.

Other Constituents

Phytochemical investigation of leaf extracts also led to the isolation of betulinic acid, β-sitosterol, and β-sitosterol glucoside, alongside flavones and flavone C-glucosides. The extract and nanoparticle preparations have been confirmed to contain phenolics, flavonoids, terpenes, and tannins. Hydrolysable tannins, including ellagic acid and related derivatives, are also characteristic of the Combretaceae family and have been identified in C. quadrangulare extracts.

A particularly notable gallic acid derivative — O-galloyl-6-O-(4-hydroxy-3,5-dimethoxy)benzoyl-β-D-glucose, isolated from C. quadrangulare, demonstrated potent hepatoprotective activity against D-GalN/TNF-alpha-induced cell death in primary cultured mouse hepatocytes.

4. Scientific Evidence by Area of Use

4.1 Anthelmintic (Antiparasitic) Activity

Evidence level: Preclinical (animal) and a limited negative human trial.

The vermifugal properties of the ripe fruits of Combretum quadrangulare were evaluated in buffalo calves after a single oral administration; a dosage of 18–54 mg/kg body weight decreased the number of Neoascaris vitulorum eggs in feces to zero in 1–3 weeks. The dried ripe seeds were ground and dissolved in water before oral administration.

In a further in vivo study on the anthelmintic activity of C. quadrangulare, the ethereal and 95% alcohol extracts of dried roots were as active as the seed extract. However, in a clinical experiment for the treatment of threadworm-infested children, negative results were obtained for moderate doses, and at a high dose negative side effects were observed.

Studies of the chemical constituents of this plant have revealed that alcoholic and other extracts from the roots and seeds could kill earthworms. The overall weight of evidence supports antiparasitic activity in animal models, but the one reported human trial yielded negative results at moderate doses and adverse effects at high doses. No robust randomized controlled trial in humans has been published.

4.2 Hepatoprotective Activity

Evidence level: Preclinical (in vitro and mouse model). No human clinical trials identified.

The MeOH extract of leaves of Combretum quadrangulare showed significant hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced experimental liver injury in mice and on D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced cell death in primary cultured mouse hepatocytes.

The flavonoids and some of the cycloartane-type triterpenes appeared to be the hepatoprotective principles of the leaves of C. quadrangulare. Quadrangularol B, methyl quadrangularate I, kumatakenin, 5,7,4′-trihydroxy-3,3′-dimethoxyflavone, 5,4′-dihydroxy-3,7,3′-trimethoxyflavone, and isokaempferide showed strong inhibitory effect on TNF-alpha-induced cell death with IC50 values of 34.3, 33.7, 13.3, 22.4, 13.4, and 22.8 µM, respectively, whereas the clinically-used silibinin had an IC50 value of 39.6 µM.

The gallic acid derivative O-galloyl-6-O-(4-hydroxy-3,5-dimethoxy)benzoyl-β-D-glucose, isolated from C. quadrangulare, also demonstrated potent hepatoprotective activity against D-GalN/TNF-alpha-induced cell death in primary cultured mouse hepatocytes. Previous studies on C. quadrangulare have mainly reported the hepatoprotective activities of its components, such as triterpenoids, sterols, and flavonoids. This body of evidence is exclusively preclinical; translation to human therapeutic outcomes has not been established.

4.3 Antimicrobial Activity

Evidence level: In vitro only.

All compounds isolated in one study had moderate (62 µg/mL) to strong (16 µg/mL) antibacterial activity (MIC values) against Staphylococcus aureus and Escherichia coli, with the most active compounds being isolated flavones and flavonols.

Compounds rhamnocitrin (4) and ombuin (5) showed moderate antibacterial activity against methicillin-resistant Staphylococcus aureus, while all compounds failed to reveal any activity toward extended-spectrum beta-lactamase-producing Escherichia coli.

Extracts from seeds display antibacterial properties. All antimicrobial studies identified are in vitro; there are no published human trials evaluating C. quadrangulare as an antimicrobial therapeutic.

4.4 Anti-HIV / Antiviral Activity

Evidence level: In vitro enzyme inhibition assay. No animal or human data.

The aqueous and ethanol extracts of C. quadrangulare were screened for their inhibitory activity against HIV-1 integrase, an enzyme essential for viral replication. The aqueous and ethanol extracts showed significant inhibitory activity against HIV-1 integrase with IC50 values of 2.5 and 2.9 µg/mL, respectively. These findings are preliminary cell-free enzyme assay results and do not establish antiviral efficacy in living systems.

4.5 Cytotoxic and Anticancer Activity

Evidence level: In vitro (cell lines) and in vitro/nanoparticle studies only. No clinical trials.

Cycloartane-type triterpenes isolated from C. quadrangulare were tested for their cytotoxicity against murine colon 26-L5 carcinoma cells; methyl quadrangularate B and methyl quadrangularate D exhibited potent cytotoxicity with ED50 values of 9.54 and 5.42 µM, respectively.

Both crude extracts and separated compounds, including cycloartane-type triterpenes and flavonoids, have shown anti-cancer activities in several cancer types; leaf methanolic extracts of C. quadrangulare Kurz inhibited KB (oral cavity) and NCI-H187 (small cell lung cancer) cell lines.

In a 2018 study, the leaf extract and prepared nanoparticles were cytotoxic to A549 lung adenocarcinoma cells; the extract had IC50 values of 257.2 and 136.1 µg/mL at 24 and 48 hours, respectively, while the nanoparticles had IC50 values of 545.2 and 350.4 µg/mL at 24 and 48 hours. C. quadrangulare nanoparticles induced apoptosis in the A549 cell line in a dose- and time-dependent manner, and at non-cytotoxic concentrations, the extract and nanoparticles inhibited the migration of A549 cells with concentration dependence.

One study specifically evaluated the cytotoxicity potentials of hexane:ethyl acetate and ethanol extracts of C. quadrangulare leaves on the HepG2 cancer cell line; using the MTT cell viability assay, both extracts demonstrated potential cytotoxicity with IC50 values of 38 and 47 µg/mL, respectively, with cell morphology changing in a dose- and time-dependent manner.

A 2011 study found that specific compounds (7, 9, 12, 16, and 17) enhanced DR5 (death-receptor 5) expression, and compound 16 showed TRAIL-resistance abrogating activity — a mechanism potentially relevant to making cancer cells susceptible to immune-mediated cell death. All anticancer evidence remains at the preclinical stage.

4.6 Alpha-Glucosidase Inhibition (Antidiabetic Potential)

Evidence level: In vitro enzyme inhibition and molecular docking. No animal or human trials.

Compounds ayanin, rhamnocitrin, and several brominated synthetic analogues from C. quadrangulare showed good alpha-glucosidase inhibition with IC50 values in the range of 30.5–282.0 µM; kinetic analysis showed that two synthetic derivatives exhibited noncompetitive inhibition against alpha-glucosidase.

These compounds exhibited good inhibition of alpha-glucosidase with IC50 values in the range of 30.5 to 282.0 µM, which was greater than the standard acarbose (IC50 332.5 µM). This suggests potential for blood sugar modulation; however, all evidence is in vitro, and no clinical translation has been demonstrated.

4.7 Anti-inflammatory and Atopic Dermatitis Activity

Evidence level: In vivo (murine model). No human clinical trials.

In a 2020 study published in Molecules, the effects of C. quadrangulare ethanol extract (CQ) were investigated on DNCB-induced atopic dermatitis-like skin lesions in BALB/c mice; after administration with CQ at 100, 200, and 400 mg/kg for 6 weeks, the CQ group improved the dermatitis score, skin pH, transepidermal water loss (TEWL), and skin hydration.

Histological analysis revealed that CQ attenuated increased epidermal thickness and mast cell infiltration; CQ also increased filaggrin expression and reduced ceramidase expression, serum IgE levels, and eosinophil numbers. CQ effectively inhibited cytokines and chemokines including IL-6, IL-13, TARC, and TSLP at the mRNA level, as well as MAPK pathway activation — including ERK, JNK, and p38 — in the skin lesions.

These findings demonstrate that CQ may be an effective treatment of AD-like skin lesions by inhibiting the expression of inflammatory mediators via the MAPK signaling pathways. This was the first published study investigating this application, and it was conducted in an animal model only.

4.8 PCSK9 Inhibition (Cardiovascular / Lipid-Lowering Potential)

Evidence level: In vitro and preliminary in vivo pharmacokinetic data. No clinical trials.

Cycloartane-type triterpenoids from C. quadrangulare have been shown to inhibit PCSK9 secretion; combretic acid A significantly inhibited the synthesis and secretion of PCSK9 and showed higher liver distribution than plasma. In vivo pharmacokinetic studies confirmed that combretic acid A exhibited higher distribution in the liver than plasma, where PCSK9 is predominantly synthesized. PCSK9 is a validated therapeutic target for LDL-cholesterol reduction, and these preliminary findings support further investigation but are far from clinical application.

5. Body Systems and Health Areas of Association

• Gastrointestinal system: Anthelmintic (roundworm, threadworm), antidysenteric, stomachache relief — the most historically documented and preclinically tested area of use.
• Hepatic system: Hepatoprotective activity demonstrated in vitro and in animal models; traditional use as antihepatitis agent in Vietnam.
• Immune and skin system: Anti-inflammatory activity in murine atopic dermatitis models via MAPK pathway modulation.
• Antimicrobial / infectious disease: In vitro activity against S. aureus (including MRSA) and E. coli; historical use for abscesses and gonorrhea.
• Antiviral: In vitro HIV-1 integrase inhibition.
• Oncology (preclinical): Cytotoxicity against colon, oral cavity, lung, and liver cancer cell lines; apoptosis induction; DR5 upregulation.
• Metabolic / endocrine: In vitro alpha-glucosidase inhibition suggesting potential antidiabetic relevance; preliminary PCSK9 inhibition relevant to cardiovascular lipid management.
• Fever and pain: Traditional antipyretic and analgesic use; preclinical data exist but are limited.

6. Dosages Reported in Scientific Studies

No standardized human dosage has been established for any indication. The following dosages appear only in their respective study contexts and should not be construed as clinical recommendations:

• Anthelmintic — animal (buffalo calves, oral): Dried ripe seeds at dosages equivalent to 18, 27, and 54 mg/kg body weight (corresponding to one-third seed, one-half seed, and one whole seed per kilogram body weight) administered as a single oral dose decreased Neoascaris vitulorum egg counts to zero in feces within 1–3 weeks.
• Atopic dermatitis — murine model (oral): Mice were administered CQ ethanol extract at 100, 200, and 400 mg/kg orally for 6 weeks.
• Hepatoprotective — in vitro: Methanol extracts demonstrated an IC50 of 56.4 µg/mL against TNF-α-induced cell death in primary mouse hepatocytes.
• Cytotoxicity against A549 lung cancer cells — in vitro: The leaf extract had IC50 values of 257.2 and 136.1 µg/mL at 24 and 48 hours, respectively; nanoparticle preparations had IC50 values of 545.2 and 350.4 µg/mL at 24 and 48 hours.
• HIV-1 integrase inhibition — in vitro: Aqueous and ethanol extracts showed IC50 values of 2.5 and 2.9 µg/mL against HIV-1 integrase.
• Traditional Thai preparation (seeds, oral): Described as grinding 3 g of seeds, mixing with egg, frying, and taking once on an empty stomach (recorded in Medicinal Plants in Thailand). This is a traditional formulation, not a validated clinical dosage.

7. Safety Considerations

Acute Toxicity

Ripe seeds of Combretum quadrangulare produced no acute toxicity in albino rats and mice when administered orally at a single dose of about 0.6 and 2 g/kg, respectively. The LD50 of an 80% methanol extract, given orally to male and female mice and male and female rats, was reported to be 3.95, 3.9, 4.4, and 3.5 g/kg, respectively.

Subchronic Toxicity

In a subchronic toxicity test, female rats given the extract at 1 g/kg/day for 4 weeks had significantly less weight gain without any changes in SGOT, SGAT, alkaline phosphatase, BUN, or serum albumin levels compared to controls. This finding of reduced weight gain at high, prolonged doses warrants attention even though classical hepatic and renal markers were unaffected.

Clinical Observation: Adverse Effects in Children

In a clinical experiment for the treatment of threadworm-infested children, negative results were obtained for moderate doses, and at a high dose negative side effects were observed. The specific nature of the adverse effects is not fully detailed in the available literature, but this finding represents the only known reported human safety signal and underscores the need for caution, particularly in pediatric populations.

Animal Study: No Body Weight Effect at Anti-inflammatory Doses

In the murine atopic dermatitis study, CQ ethanol extract had no effect on body weight compared to the normal group at doses of 100–400 mg/kg over 6 weeks, suggesting reasonable tolerability at the tested doses in mice.

Overall Evidence Status and Absence of Human Trials

Most of the available evidence is derived from preclinical studies, and robust human clinical trials are still limited. While no serious adverse effects have been reported in the available literature beyond the pediatric anthelmintic experiment, further research is needed to fully establish its safety profile and therapeutic efficacy in humans. Exhaustive research regarding the isolation of more phytochemicals and pharmacology study on this medicinal plant is still necessary for exploration of the plant regarding its medicinal importance.

Drug Interactions

No peer-reviewed data on pharmacokinetic drug interactions (e.g., cytochrome P450 enzyme effects) for C. quadrangulare in humans have been identified in the published literature at the time of this writing. The presence of potent flavonoids and tannins — compound classes known in other plants to interact with drug-metabolizing enzymes — is a theoretical consideration that has not been specifically investigated for this species.

8. Overall Evidence Assessment

Combretum quadrangulare has a well-documented historical role in Southeast Asian traditional medicine, with anthelmintic and hepatoprotective uses having the most consistent cross-cultural documentation and the largest body of preclinical investigation. The traditional uses have been corroborated by in vitro data of hepatoprotective, antipyretic, analgesic, antidysenteric, and anthelmintic properties. Multiple research groups working in Vietnam, Thailand, Japan, and Korea have characterized a rich and chemically diverse phytochemical profile, identifying over 97 compounds including novel cycloartane triterpenes and flavones with demonstrated biological activity across multiple assay systems.

However, the evidence base remains firmly preclinical. The sole reported human trial — an anthelmintic study in children — produced negative results at moderate doses and adverse effects at high doses. No published randomized controlled trials, systematic reviews, or formal clinical efficacy assessments exist for any indication. The discovery of PCSK9-inhibitory activity, DR5 upregulation, alpha-glucosidase inhibition, and MAPK-mediated anti-inflammatory effects represents emerging and scientifically interesting directions, but none of these have been studied in humans. The overall level of evidence for C. quadrangulare as a therapeutic agent in any human condition must therefore be characterized as preliminary and insufficient to draw clinical conclusions.

References

• Flavones from Combretum quadrangulare Growing in Vietnam and Their Alpha-Glucosidase Inhibitory Activity — PMC / Molecules (2021)
• Combretum quadrangulare Extract Attenuates Atopic Dermatitis-Like Skin Lesions through Modulation of MAPK Signaling in BALB/c Mice — PMC / Molecules (2020)
• Bioactivities of the Genus Combretum (Combretaceae): A Review — PMC
• Hepatoprotective effect of Combretum quadrangulare and its constituents — PubMed
• Cycloartane triterpenes isolated from Combretum quadrangulare in a screening program for death-receptor expression enhancing activity — PubMed / Journal of Natural Products (2011)
• Cycloartane-type triterpenoids from Combretum quadrangulare Kurz with PCSK9 secretion inhibitory activities — Phytochemistry (2025)
• Nanoparticles of Combretum quadrangulare leaf extract induce cytotoxicity, apoptosis, cell cycle arrest and anti-migration in lung cancer cells — Journal of Drug Delivery Science and Technology (2018)
• Combretum quadrangulare (Combretaceae): Phytochemical Constituents and Biological Activity — ResearchGate / Indo American Journal of Pharmaceutical Research (2014)
• Combretum quadrangulare — PROSEA: Plant Resources of South East Asia
• Studies on anthelmintic activity of Sakae Na (Combretum quadrangulare Kurz) seeds on round worms of buffalo calves — AGRIS/FAO
• Combretum quadrangulare — Grokipedia (citing primary botanical sources)
• Combretum quadrangulare — HandWiki Biology
• Combretum quadrangulare — Wikipedia