Alstonia macrophylla

Alstonia macrophylla Wall. ex G. Don

1. Identity and Botanical Description

Scientific Name and Taxonomy

Alstonia macrophylla Wall. ex G. Don is a flowering tree in the family Apocynaceae (the dogbane family). It is formally designated Alstonia macrophylla Wall. ex G. Don, belonging to the family Apocynaceae. Accepted botanical synonyms include Alstonia cuneata Wall. ex G. Don and Alstonia cochinchensis Pierre ex Pit.

Common Names and Vernacular Designations

The tree is known in English as "hard milkwood" or "Siamese balsa," as pulai gabus in Indonesia, pulai basong in Malaysia, tinpet phru in Thailand, and sua la bang in Vietnam. The species is also referred to as "hard alstonia" or "big-leaved macrophyllum," and is native to Indonesia (Kalimantan and Sulawesi), Malaysia, the Philippines (Tagalog: batino), Thailand, and Vietnam. It was introduced to Sri Lanka, where it is known as hawari nuga by local Sinhalese people.

Morphological Description

It is a tree which grows to a height of 24 m in forests across a geographical area ranging from Myanmar to Papua New Guinea. The tree has a straight trunk and a high, narrow crown, and can grow up to 30 meters tall. The trunk and branches contain a white latex, and the bark is smooth with a light grey color. Leaves are in whorls of three to four, simple, penni-veined, membranous, and glabrous above, with leaf-blades 10 to 50 centimetres long and 5 to 15 cm wide, widest in or above the middle and cuneate at the base. Flowers are about 7 mm in diameter, white, with a narrow corolla tube, placed terminally on twigs. Fruits are about 30 centimetres long, green, and filled with many small hairy seeds that are dispersed far and wide by the wind.

Position within the Genus

The genus Alstonia comprises about 60 species throughout the world, with about 6 species occurring in India. Among them, Alstonia scholaris, Alstonia macrophylla, and Alstonia venenata R. Br. have medicinal importance.

Relationship to Alstonia scholaris and the Adulteration Problem

Both Alstonia scholaris and Alstonia macrophylla share many characteristics such as tree habit, milky latex, simple entire petiolate leaves, whorled phyllotaxy, small flowers, cymose inflorescence, calyx, pubescent corolla, and follicle fruits. These phenotypic similarities sometimes create confusion among plant collectors and common users, and A. scholaris is often adulterated with A. macrophylla. In India, despite its limited distribution, the bark of Alstonia macrophylla is used as a substitute for Alstonia scholaris bark in herbal pharmaceutical preparations. However, recent studies have demonstrated that both species are distinct from each other in their phytochemistry and pharmacology. Alkaloids reported in the bark of A. scholaris are almost different from those of A. macrophylla, and compared to A. scholaris, the number of bioactive alkaloids reported in the stem bark of A. macrophylla is also larger, which may be the reason that in most comparative pharmacological studies, the bark of A. macrophylla proves more potent than that of A. scholaris.

Common Forms and Preparations

In both traditional and research settings, preparations of A. macrophylla have been derived from several plant parts. Ethnobotanical reports indicated that decoctions of Alstonia macrophylla leaves and stem bark were widely used in the treatment of stomachache, skin diseases, and urinary infections. The root bark has been the subject of the most intensive phytochemical and pharmacological work, with methanol extracts being the most common solvent-based preparation in scientific studies. Eight constituents were detected in crude dichloromethane (DCM) extracts of the bark, consisting of a long-chain unsaturated fatty acid and fatty acid esters such as ethyl hexadecanoate and methyl hexadecanoate. Extraction of the bark using methanol and dimethyl sulfoxide (MeOH/DMSO) solvents resulted in the identification of 17 constituents, principally alkaloids (alstonerine, 34.38%; strictamin, 5.23%; rauvomitin, 4.29%; and brucine, 3.66%) and triterpenoids (γ-sitosterol, 3.85%; lupeol, 3.00%; 24-methylenecycloartanol, 2.81%; campesterol, 2.71%; β-amyrin, 2.30%; and stigmasterol, 2.13%).

2. Traditional and Historical Use

Southeast Asian Traditional Medicine

Alstonia macrophylla has been used in conventional medicines in Thailand, Malaysia, and the Philippines as a general tonic, aphrodisiac, anticholeric, antidysentery, antipyretic, emmenagogue, and vulnerary agent. In the tribes of the Indian Gulf Islands, the leaves of Alstonia macrophylla Wall. ex G. Don are commonly decocted to treat stomach pains.

Indian Traditional Use

In India, Alstonia macrophylla has been used as a substitute for Alstonia scholaris in various herbal pharmaceutical preparations. The broader genus is documented in traditional medical systems across the subcontinent, and both Alstonia scholaris and Alstonia macrophylla have been extensively used in traditional medicinal systems of India, Thailand, Malaysia, the Philippines, China, Africa, and Australia.

Specific Traditional Applications

Ethnobotanical reports indicate that decoctions of Alstonia macrophylla leaves and stem bark were widely used in the treatment of stomachache, skin diseases, and urinary infections. The traditional use of the plant as an antipyretic connects to its documented employment against malaria and febrile illnesses, while its use as a vulnerary (wound-healing agent) and emmenagogue (menstrual stimulant) represents additional applications recorded by ethnobotanists. Beyond these uses, the traditional application of Alstonia species — including A. macrophylla — in the treatment of malaria remains little explored scientifically.

3. Key Constituents and Active Compounds

Overall Phytochemical Profile

Alstonia macrophylla is rich in different types of bioactive alkaloids. At least 400 compounds have been isolated from the genus Alstonia, including alkaloids, triterpenes, flavonoids, volatile oils, and phenolic acids. In the case of A. macrophylla specifically, alkaloids — particularly of the indole type — are the most intensively studied chemical class. Both A. macrophylla and A. scholaris have been reported to contain echitovenidine, echitamine, venenatine (an indole alkaloid), and anti-inflammatory triterpenoids.

Indole and Bisindole Alkaloids

The indole alkaloids of A. macrophylla are dominated by both monomeric and dimeric (bisindole) structures. A new alkaloid, 19-hydroxyvincamajine, has been isolated from the leaves of Alstonia macrophylla. In addition, eight other indole alkaloids — alstonerine, alstophylline, macralstonine, anhydromacralstonine, talcarpine, vincamajine, vincorine, and cabucraline — were isolated and identified from the bark and leaves of A. macrophylla from Sri Lanka.

The root bark of Alstonia macrophylla from Thailand provided several new bisindoles, namely alstomacrophylline, alstomacroline, and O-methylmacralstonine, in addition to the known bisindoles macralstonine, macrocarpamine, villalstonine, and its N(4)-oxide.

Two new oxindole alkaloids — N_b-demethylalstophyllal oxindole and alstonal — together with three known alkaloids, N_b-demethylalstophylline oxindole, alstonisine, and talcarpine, have been isolated from the bark of Alstonia macrophylla.

The bark of A. macrophylla Wall. contains, in addition to five known alkaloids (villalstonine, macralstonine, macralstonidine, macrophylline, and Alkaloid M), a new tertiary base, alstophylline (C₂₂H₂₆N₂O₃), and a quaternary alkaloid.

Bisindoles as Structurally Distinctive Constituents

Bisindoles are structurally complex dimers and are intriguing targets for partial and total synthesis. They exhibit stronger biological activity than their corresponding monomeric units. The bisindole alkaloids macrocarpamine, villalstonine, and macralstonine are among the most pharmacologically significant compounds identified in A. macrophylla.

Secoiridoid Glycosides

The ethanolic extract from stems of A. macrophylla showed a significant inhibitory effect on acetylcholinesterase (AChE) determined using the Ellman assay. Four compounds were isolated: a bisindole alkaloid, macralstonine; a new bisindole alkaloid, thungfaine; a secoiridoid glycoside, sweroside; and a new secoiridoid glycoside, naresuanoside. Compound naresuanoside showed moderate AChE and butyrylcholinesterase (BChE) inhibitory effects.

Triterpenoids and Other Constituents

Analysis of bark extracts using MeOH/DMSO solvents confirmed the presence of triterpenoids including γ-sitosterol, lupeol, 24-methylenecycloartanol, campesterol, β-amyrin, and stigmasterol. Lupeol and related triterpenoids are known from the broader Alstonia genus and are associated with anti-inflammatory and cytotoxic activities.

4. Mechanisms of Action

Antiplasmodial Mechanism

The antiplasmodial activity of A. macrophylla alkaloids is attributed primarily to the bisindole alkaloids. Methanol extracts prepared from various parts of Alstonia scholaris, A. macrophylla, and A. glaucescens from Thailand were assessed for antiplasmodial activity against the multidrug-resistant K1 strain of Plasmodium falciparum cultured in human erythrocytes. Pronounced antiplasmodial activity was exhibited by the methanol extract of the root bark of A. macrophylla with an IC₅₀ value of 5.7 μg/ml. Thirteen indole alkaloids were isolated from the active extract. These alkaloids and a semisynthetic bisindole O-acetylmacralstonine were subsequently tested against the K1 strain of P. falciparum, and pronounced antiplasmodial activity was observed mainly among the bisindole alkaloids, particularly villalstonine and macrocarpamine, with IC₅₀ values of 0.27 and 0.36 μM, respectively. The active alkaloids, in contrast to chloroquine, showed significantly higher affinity to the drug-resistant K1 strain than to the chloroquine-sensitive T9-96 strain.

Cytotoxic and Antiproliferative Mechanism

Thirteen indole alkaloids isolated from the root bark of Alstonia macrophylla and a semisynthetic bisindole O-acetylmacralstonine were assessed for cytotoxic activity against two human lung cancer cell lines, MOR-P (adenocarcinoma) and COR-L23 (large cell carcinoma), using the SRB assay. Pronounced cytotoxic activity was exhibited by the bisindoles on both cell lines, suggesting that, in comparison with the corresponding monomeric indoles, at least part of both ring systems present in the bisindoles is essential for cytotoxic activity. The potent alkaloids were further tested against a normal human cell line (breast fibroblasts) and other human cancer cell lines including StMI1 1a (melanoma), Caki-2 (renal cell carcinoma), MCF-7 (breast adenocarcinoma), and LS174T (colon adenocarcinoma). The bisindoles O-acetylmacralstonine, villalstonine, and macrocarpamine were found to possess pronounced activity against cancer cell lines with IC₅₀ values in the range of 2–10 μM.

Acetylcholinesterase (AChE) Inhibitory Mechanism

The ethanolic stem extract of A. macrophylla showed significant inhibitory effects on acetylcholinesterase (AChE) as determined by the Ellman assay. The newly identified secoiridoid glycoside naresuanoside showed moderate AChE and butyrylcholinesterase (BChE) inhibitory effects. Acetylcholinesterase inhibition is a recognized mechanism relevant to cognitive disorders such as Alzheimer's disease, making this finding of interest for future neurological investigations, though no clinical data in humans have been published for this species.

Antioxidant Mechanism

In laboratory work on Philippine A. macrophylla bark, the extract was found to be an efficient antioxidant. Antioxidant effects in Alstonia species are generally attributed to the phenolic content and indole alkaloid components, including those with electron-donating structural features capable of neutralizing reactive oxygen species.

Broad Pharmacological Profile of the Genus

Through extensive pharmacological experiments, it was demonstrated that genus Alstonia has good pharmacological effects in vitro and in vivo, including β₂-adrenergic receptor (β₂AR) activity, vasodilatory, antifungal, antineoplastic, antiplasmodial, anti-inflammatory, antibacterial, antioxidant, analgesic, and radioprotective activities.

5. Scientific Evidence by Area of Use

5.1 Antimalarial / Antiplasmodial Activity

Evidence type: In vitro; no human clinical trials identified.

In one comparative study, it was found that Alstonia macrophylla had more potent antiplasmodial activity than Alstonia scholaris against the multidrug-resistant K1 strain of Plasmodium falciparum cultured in human erythrocytes, and among all plant parts tested, the root bark of Alstonia macrophylla showed the most marked antiplasmodial activity. The key in vitro benchmark was established by Keawpradub et al. (1999): the methanol extract of the root bark exhibited pronounced antiplasmodial activity with an IC₅₀ of 5.7 μg/ml; 13 indole alkaloids were isolated, and subsequently the bisindole alkaloids villalstonine and macrocarpamine showed IC₅₀ values of 0.27 and 0.36 μM, respectively, against the K1 strain.

Further detail studies are essential to well establish the antimalarial potential of Alstonia macrophylla, especially for isolating the antimalarial active principle. No in vivo animal studies or human clinical trials have been published specifically for A. macrophylla as an antimalarial; the evidence base therefore remains at the preliminary in vitro level.

5.2 Anticancer / Cytotoxic Activity

Evidence type: In vitro cell line studies; no human clinical trials identified.

Indole derivatives found in the rhizome outer covering of A. macrophylla had antiproliferative action (using the SRB assay) on MOR-P and COR-L23 carcinomas because of the bisindole component. O-Acetylmacralstonine, villalstonine, and macrocarpamine were also established to influence specific actions on normal mammary fibroblasts, as well as on immortalized cancers: StMl1 1a (skin cancer), Caki-2 (kidney cancer), MCF-7 (breast cancer), and LS174T (colon cancer), with IC₅₀ values ranging 2–10 μM.

In a study of the Philippine bark, the assessment of the effectiveness of A. macrophylla (AM) on four immortalized cancer cell lines revealed that the integrity of MCF-7, H69PR, and HT-29 cells consistently decreased in all trials. Both Alstonia scholaris and Alstonia macrophylla are rich in different types of bioactive alkaloids, and a broad spectrum of in vitro and in vivo biological and pharmacological activities have been reported for both species, with antimicrobial and anticancer activities being among the most promising.

All cytotoxic evidence is from cell culture experiments. No clinical translation to human cancer treatment has been demonstrated. The IC₅₀ values reported are in vitro benchmarks and do not represent therapeutic doses in humans.

5.3 Antimicrobial Activity

Evidence type: In vitro; preliminary.

Ethnobotanical reports indicated that decoctions of Alstonia macrophylla leaves and stem bark were widely used in the treatment of stomachache, skin diseases, and urinary infections. Comparative phytochemical and antibacterial studies on the bark of A. scholaris and A. macrophylla have been conducted (Khyade and Vaikos, 2010, Pharmacognosy Journal), but detailed species-specific antibacterial data from those studies are not accessible in current open sources. The broader genus shows documented antifungal and antibacterial properties in multiple in vitro models.

5.4 Antioxidant Activity

Evidence type: In vitro; preliminary.

The antioxidant activity of crude A. macrophylla bark extracts was established in vitro using a modified DPPH (1,1-diphenyl-2-picrylhydrazyl) assay. Antioxidant effects have been confirmed in the Philippine bark material in a single laboratory study (Tan et al., 2019, ACS Omega). The evidence is based on cell-free and cell-based in vitro methods and has not been tested in human subjects.

5.5 Acetylcholinesterase Inhibition (Neuroprotective Potential)

Evidence type: In vitro enzyme assay; preliminary.

The ethanolic stem extract of Thai A. macrophylla showed a significant inhibitory effect on acetylcholinesterase. Four compounds were isolated including the new secoiridoid glycoside naresuanoside, which showed moderate AChE and BChE inhibitory effects and inhibited cell growth on a human androgen-sensitive prostate cancer cell line (LNCaP) with no effect on the viability of human foreskin fibroblast cells. This represents preliminary evidence only; no animal or human studies on AChE inhibition by A. macrophylla have been published.

5.6 Anti-inflammatory Activity

Evidence type: Preclinical; preliminary.

A published study evaluated the anti-inflammatory activity of Alstonia macrophylla Wall. ex A. DC. leaf extract (ScienceDirect, 2004). Both A. macrophylla and A. scholaris have been reported to contain echitovenidine, echitamine, venenatine (an indole alkaloid), and anti-inflammatory triterpenoids. The triterpenoid constituents identified in A. macrophylla bark — particularly lupeol and β-amyrin — are compound classes with established anti-inflammatory profiles in the broader phytochemical literature, but species-specific human data are absent.

5.7 Antiophidian (Anti-snake venom) Activity

Evidence type: In vitro; single study; preliminary.

The antiophidian (antivenom) activity of crude A. macrophylla bark extracts was among the bioassays conducted in the 2019 ACS Omega study, which evaluated Philippine bark material. This represents a novel pharmacological direction for the species, but the findings remain at an early in vitro stage with no in vivo confirmation.

Summary of Evidence Strength

All pharmacological evidence for Alstonia macrophylla at the time of the most recent peer-reviewed publications is based on in vitro cell culture and biochemical assays, or limited preclinical animal data. No randomized controlled human clinical trials, systematic reviews, or regulatory approvals have been identified for Alstonia macrophylla as a therapeutic agent or dietary supplement. The body of work is therefore best characterized as preliminary, mechanistically interesting, and warrant-generating for further research, rather than clinically actionable evidence.

6. Body Systems and Health Areas of Association

• Immune and Infectious Disease: Antiplasmodial activity (malaria, particularly multidrug-resistant P. falciparum); traditional use as an antipyretic and anticholeric agent.
• Oncology (Preclinical): In vitro cytotoxicity against lung, breast, kidney, colon, and skin cancer cell lines via bisindole alkaloid constituents.
• Gastrointestinal System: Traditional use for stomachache, dysentery, and cholera-related symptoms via decoctions.
• Neurological System (Preclinical): AChE and BChE inhibition by secoiridoid constituents; potential relevance to cholinergic disorders.
• Reproductive System: Traditional use as an emmenagogue (menstrual stimulant) and aphrodisiac in Southeast Asian folk medicine.
• Dermatological System: Traditional use for skin diseases; vulnerary (wound-healing) properties documented ethnobotanically.
• Urinary System: Traditional use in urinary infections via bark and leaf decoctions.
• Oxidative Stress: In vitro antioxidant activity demonstrated with DPPH assay on bark extracts.

7. Dosage Forms and Reported Dosages in Studies

No standardized dosage forms for human consumption have been established for Alstonia macrophylla. The following dosage parameters have appeared in primary research literature:

• In vitro antiplasmodial studies: Pronounced antiplasmodial activity was exhibited by the methanol extract of the root bark with an IC₅₀ value of 5.7 μg/ml. The bisindole alkaloids villalstonine and macrocarpamine showed IC₅₀ values of 0.27 and 0.36 μM, respectively, against the K1 strain of P. falciparum.
• In vitro cytotoxicity studies: The bisindoles O-acetylmacralstonine, villalstonine, and macrocarpamine demonstrated cytotoxic activity against multiple human cancer cell lines with IC₅₀ values in the range of 2–10 μM.
• Traditional decoction: Decoctions of A. macrophylla leaves and stem bark were widely used in traditional systems. No standardized concentration or quantity for traditional decoctions has been documented in the peer-reviewed sources accessed.

All IC₅₀ values given are in vitro benchmarks only. No human pharmacokinetic data, bioavailability parameters, or established therapeutic dose ranges have been published for Alstonia macrophylla.

8. Safety Considerations and Notable Interactions

Alkaloid Toxicity Potential

Some plant components in the Alstonia genus, especially the latex and certain alkaloids, are known to have toxic effects, underscoring the importance of proper preparation and controlled dosage. A. macrophylla bark has been confirmed to contain brucine (3.66% of MeOH/DMSO extract constituents in one analysis), a strychnine-related alkaloid with well-documented neurotoxicity. The presence of brucine is a significant safety concern for preparations derived from this species.

Toxicology Data (Genus-Level, from A. scholaris)

Formal toxicology studies have been conducted on indole alkaloid extracts of the closely related Alstonia scholaris, not on A. macrophylla directly. These studies are cited here as contextually relevant but are species-specific to A. scholaris:

In acute toxicity tests in mice using A. scholaris total alkaloids (TA), a single high-dose administration produced behavioral effects, and at 12.8 g/kg bw, prone position, shortness of breath, wheezing, and convulsion were observed. The LD₅₀ in mice was 5.48 g/kg bw — approximately 2,740 times the clinical dose in humans. Among five indole alkaloids tested individually, the maximum tolerance dose in mice ranged from 0.75 to 4 g/kg bw.

In chronic toxicity tests, TA-treated rats did not die and showed no adverse effects or dose-dependent changes in weight or food and water consumption. Both gross and histopathological observations revealed no abnormalities in any organ. The non-observed-adverse-effect level (NOAEL) of TA was 100 mg/kg bw with daily oral administration to rats, and the results indicated that TA is safe for clinical use at this dose level.

Genotoxicity (A. scholaris Indole Alkaloid Extract)

No abnormal neurobehavioral effects were observed in mice following treatment with up to 960 mg/kg bw of indole alkaloid extract (IAAS) from A. scholaris. Blood pressure, heart rate, electrocardiogram parameters, and depth and rate of breathing in anesthetized beagle dogs did not differ among IAAS doses or from the vehicle group. These data indicated that IAAS did not induce mutagenicity, clastogenicity, or genotoxicity, and no pharmaco-toxicological effects were observed in the respiratory, cardiovascular, or central nervous systems. Again, these findings pertain specifically to A. scholaris and may not be directly extrapolated to A. macrophylla.

Species Substitution and Adulteration Risk

The use of Alstonia macrophylla as a substitute for Alstonia scholaris is not at all justifiable, as both species are distinct from each other in their phytochemistry and pharmacology. Further detailed chemical fingerprinting and metabolic studies of these two species are warranted to prevent their mutual adulteration, most importantly in the context of commercial preparations. This is a direct, evidence-based safety concern: commercial herbal preparations labeled as A. scholaris may contain A. macrophylla, or vice versa, with potentially different pharmacological profiles and safety implications.

Limited Toxicity Data Specific to A. macrophylla

Only a few studies have addressed the toxic potential of Alstonia scholaris and Alstonia macrophylla specifically. No species-specific LD₅₀ data, human safety data, or drug interaction data have been reported for A. macrophylla in the peer-reviewed literature accessed. Given the presence of potent alkaloids including brucine and multiple bisindoles with documented in vitro bioactivity, the absence of safety data is a notable gap. No government regulatory body (FDA, EMA, WHO) has issued a formal monograph or safety assessment for Alstonia macrophylla as of the current literature record.

Known or Plausible Interactions

No formal drug-interaction studies have been published for A. macrophylla. On mechanistic grounds, the AChE-inhibitory constituents identified in ethanolic stem extracts present a theoretical concern for additive or competitive interaction with cholinesterase-inhibiting pharmaceutical drugs (e.g., donepezil, rivastigmine). The antiplasmodial bisindoles have shown selectivity for the multidrug-resistant K1 strain of P. falciparum at concentrations distinct from chloroquine, but no pharmacokinetic or drug-interaction data have been published.

References

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