Abstract

Goniothalamus sesquipedalis, a rare species within the Annonaceae family, has garnered significant attention for its traditional medicinal uses and bioactive compounds. This plant is native to tropical Southeast Asia and is widely recognized for its efficacy in treating ailments such as fever, diarrhea, and body pains. Phytochemical screening has identified a range of compounds including alkaloids, flavonoids, glycosides, and sterols, which contribute to its medicinal properties. Bioactivity assays have demonstrated the plant's antibacterial, antioxidant, and analgesic activities, making it a potential source of natural pharmaceutical agents. Ethnomedicinal studies have highlighted the plant's cultural and health-related significance in traditional practices, particularly in Manipur, India, where it is used in various forms, including decoctions and steams, to treat various ailments. Despite its promising results, further research is needed to fully understand the plant's bioactive compounds, molecular mechanisms, and in vivo performance. This review aims to integrate available data, discuss conflicts of interest, and identify areas of further research to better utilize this plant's potential in traditional and modern medicine.

Keywords

Introduction

The genus Goniothalamus, part of the Annonaceae family, encompasses around 160 species [1,2]. This diverse genus thrives in the lowland and submontane forests of tropical Southeast Asia, particularly in Western Malesia, Sumatra, and Peninsular Malaysia, showcasing a remarkable adaptability to various environments [3–5]. In India alone, over 10 species of Goniothalamus demonstrate the genus' extensive habitat range [6]. The medicinal potential of these plants is noteworthy, with some species traditionally used for ailments such as body pains, fever, and rheumatism, and for their anti-aging and abortifacient properties [6,7]. The bioactive compounds in these plants, including acetogenins, styryl-lactones, and alkaloids, have shown cytotoxic and antimicrobial properties, reinforcing their use in traditional Asian medicine for cancer and infection treatments [8–12]. Goniothalamus sesquipedalis stands out for its notable use in traditional medicinal practices in Manipur, India. It is utilized in various forms, such as decoctions and steams from medicinal concoctions, particularly for its efficacy in treating ailments like fever and diarrhea [13]. This usage underscores its importance in community health management across several districts in Manipur, where it also serves as an analgesic and even plays roles in rituals, showcasing its broad application spectrum [14,15]. And, goniothalamin, a staple compound in many goniothalamus species has been noted for its anticancer, antioxidant, and anti-viral properties [16–18]. A very rare species amongst these studies is Goniothalamus sesquipedalis which, despite a few preliminary screenings and assays [19,20],  has not been as extensively examined in terms of identifying its bioactive compounds through mass spectrometry or other techniques of higher sensitivity, their molecular mechanisms of bioactive compounds through molecular docking and in vivo performance through animal models and so on. However, the results from these existing studies are very promising. Its methanol extract was first studied for its importance in traditional medicine in North East India and then, further proved to be a potential source of antibacterial agents [20]. Phytochemical screening of both the methanol and ethanol extracts revealed the presence of alkaloids, flavonoids, tannins, phlobatannin, glycosides, and sterols in its seeds, highlighting its potential as an analgesic agent [19,20]. Traditions corroborate such findings, it has been used as an analgesic, and its methanolic extracts have shown antibacterial effects, particularly against E. coli in places where it's available [21]. Essential oils from various Goniothalamus species, containing sesquiterpenoids and monoterpenoids, contribute to their aromatic and medicinal attributes [20]. Meanwhile, Compounds isolated from related Goniothalamus species, such as goniotriol and pinocembrin, have demonstrated anti-HIV-1 RT inhibition and cytotoxic activities against different cell lines, indicating potential therapeutic benefits [9,22].  The exploration into the phylogenetics of Goniothalamus sesquipedalis has provided further insights into its evolutionary context within the Annonaceae family. Studies such as those by Tang et al. (2013) and, within a bioproject, have employed nuclear gene sequencing to elaborate on the phylogenetic relationships and diversification among Annonaceae members [4,23,24]. This phylogenetic framework helps in understanding the genetic lineage and potential adaptive traits of Goniothalamus sesquipedalis, offering a broader evolutionary perspective that supports its pharmacological research [23,24]. Although not a large collections, some compounds have been identified from Goniothalamus sesquipedalis, research has shown the isolation of specific bioactive compounds like Goniopedaline and Aristololactam A-II from the plant [22,25,26]. These compounds have been analyzed for their pharmacological properties, emphasizing their potential therapeutic benefits, particularly in anticancer and antimicrobial activities. The ADMET properties of these compounds were specifically reviewed, revealing challenges such as low solubility and high plasma protein binding that could affect their therapeutic applications [27,28]. Therefore, in the interest of highlighting a potential, natural pharmaceutical agent in this rare species, this review will compare and integrate available data as a potential pharmaceutical agent, discuss conflicts of interest in the pursuit of studying this species, briefly call back to the use of Goniothalamus specied, including G. sesquipedalis, in traditional medicine and most importantly, point out missing information and areas of further research to be done.

A BRIEF HISTORY OF GONIOTHALAMUS SESQUIPEDALIS IN ETHNOMEDICINAL USE:

Ethnomedicine, passed down through generations via knowledge, skills, and beliefs, is widely used by tribal, non-tribal, and rural populations who rely on ethnoflora for various treatments [29–31]. Ethnobotanical studies provide valuable insights into these traditional medicinal practices [29]. In all countries around the world, over time, these practices evolved into codified systems like Ayurveda, Siddha, Unani, and Sowa-Rigpa [32–35].  In the realm of ethnomedicine, Goniothalamus is present throughout. For instance, Goniothalamus was among 71 different plants used for ethnomedicine in Tonga [36]. And, in Asia, Goniothalamus species are widely recognized for their medicinal uses across the southeast countries [37]. Goniothalamus macrophyllus is traditionally used in Malaysia and Indonesia as a fever remedy and general health tonic [37–39]. In the Bukit Pembarisan forest, West Java, G. macrophyllus is highly valued by local communities, with its population structure influenced by factors like soil nitrogen and pH [38]. In the Philippines, Goniothalamus amuyon is valued for its anti-inflammatory properties and its utility in treating various skin conditions [22]. In Thailand, other Goniothalamus species like G.roseipetalus, G.sukhirinensis, and G.macrophyllus are highlighted for their traditional, medicinal significance in pain relief and infection treatment [40]. Goniothalamus giganteus, used in Vietnam, is known for treating digestive issues and stomach aches, highlighting its significance in traditional medicinal systems[22]. And,  Goniothalamus fulvus, is similarly employed for its health benefits in various Southeast Asian countries [37]. There is numerous other instances of traditional usage of Goniothalamus species in ethnomedicine throughout the world and a more comprehensive and detailed account is given in an earlier review [6]. In a similar capacity, Goniothalamus sesquipedalis has been integral to the traditional medicinal practices in the Indian north-eastern state of Manipur, showcasing a variety of uses proving its cultural and health-related importance throughout many districts of the state. Among the people of Senapati district, this plant is a key component of medicinal concoctions [13]. The steam from these concoctions is used to treat common ailments such as fever and diarrhea [13], reflecting the plant's role in community health management. In the Bishnupur district, specifically within the Chothe tribe, Goniothalamus sesquipedalis serves multiple functions—not only as an insecticide and blood purifier but also in rituals to drive away spirits [14], indicating its deep-rooted significance in both the practical and spiritual lives of the community. Moreover, in the Thoubal district of Manipur, where the plant is sparsely distributed, it plays a unique role in neonatal care [15]. A decoction made from this plant is traditionally used as a bath for newborn children, which is believed to impart protective health benefits [15], safeguarding the well-being of the most vulnerable members of the society. An overview of the uses in Manipur is given Table 1.

Table 1: Ethnomedicinal Uses of Goniothalamus sesquipedalis in Manipur, India

Adding to its medicinal repertoire, Goniothalamus sesquipedalis is traditionally recognized for its analgesic properties as it is also widely used in traditional medicine across the different regions around asia to alleviate pain, providing a natural alternative to synthetic pain relievers [19]. These diverse applications of Goniothalamus sesquipedalis in Manipur not only exemplify the plant's versatility in traditional medicine but also its enduring relevance in the healthcare practices of indigenous communities. This aligns with the broader patterns observed in other regions where Goniothalamus species are employed, reinforcing the global importance of ethnomedicine in contemporary health systems and the need for continued ethnobotanical research to preserve and understand these invaluable traditional knowledge systems

OVERVIEW OF BIO-ACTIVITY STUDIES DONE WITH GONIOTHALAMUS SESQUIPEDALIS:

Research on Goniothalamus sesquipedalis has progressively unveiled its diverse pharmacological properties, indicating its significant potential in both traditional and modern medicine. The exploration into the ethnomedicinal applications of this plant began with studies focused on its antibacterial properties. For instance, Konsam et al. (2015) investigated the antibacterial activities of the plant's methanolic extracts against Bacillus subtilis and Escherichia coli, finding significant inhibition zones that confirmed its efficacy [20]. The study highlighted the presence of key phytochemicals such as alkaloids, flavonoids, and terpenoids, which contribute to its medicinal value [20]. However, the study was limited by its focus on only two bacterial strains, which may not fully represent the plant's antibacterial potential against a broader spectrum of pathogens [20]. Building on the foundational antibacterial studies, Khan et al. (2018) performed a detailed phytochemical screening of Goniothalamus sesquipedalis, identifying a wide range of active compounds including alkaloids, flavonoids, glycosides, and sterols [19]. This study provided a scientific basis for the plant’s use as an analgesic agent in traditional medicine, further broadening our understanding of its bioactive components. However, the study's main drawback was its lack of in vivo testing, which is crucial for confirming the efficacy and safety of these phytochemicals in biological organisms [19]. The scope of research expanded further with the work of Rahman et al. (2019), who explored both the antimicrobial and antioxidant activities of the plant. Their study demonstrated that the ethanol extract of Goniothalamus sesquipedalis not only continued to show substantial antimicrobial activity against pathogens such as E. coli but also exhibited notable antioxidant capabilities, adding an additional layer of therapeutic potential [41]. Despite these findings, the study did not explore the mechanisms underlying these effects, which are essential for developing targeted therapies [42]

Most recently, Habiba et al. (2019) delved into the anthelmintic and insecticidal properties of the plant. Their research revealed significant dose-dependent anthelmintic activity against earthworms and high insecticidal activity against Sitophilus oryzae, showcasing the plant's versatility and broadening its range of potential applications beyond merely antibacterial and antioxidant uses. One limitation of this study, however, was its focus on a single insect species, which might not provide a complete picture of the plant's insecticidal range [43].

G. SESQUIPEDALIS EXHIBITS SIGNIFICANT ANTIBACTERIAL ACTIVITY:

The antimicrobial activities of Goniothalamus sesquipedalis have been thoroughly explored through several studies, employing various methodologies and targeting different microbial strains. These investigations have focused primarily on antibacterial properties, with less emphasis or data available on antifungal effects.

Konsam et al. (2015) initiated a focused investigation into the antibacterial properties of Goniothalamus sesquipedalis using methanolic extracts. Employing the well-diffusion method, a common technique for assessing antimicrobial activity, the study measured the inhibition zones produced by the extracts against two bacterial strains: Bacillus subtilis and Escherichia coli. The well-diffusion method involves applying the extract to wells punched in agar plates pre-inoculated with the bacterial strains [41]. The effectiveness is evaluated by measuring the diameter of the inhibition zones formed around the wells, indicating the extent to which the bacterial growth has been hindered [44,45]. This method provides a visual and quantitative measure of antimicrobial potency. The study showed significant inhibitory effects against both bacterial strains [20], suggesting a broad spectrum of activity within the bacterial domain. However, it did not explore antifungal activity, leaving a gap in the understanding of the plant's efficacy against fungal pathogens [20]. Rahman (2019) extended the analysis of the antimicrobial properties of Goniothalamus sesquipedalis by using ethanol extracts and incorporating both the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay for antioxidant activity and the well-diffusion method for antimicrobial testing [42]. This study also targeted Escherichia coli, using the same well-diffusion technique to assess the inhibition zones. Additionally, the antioxidant capabilities were evaluated using the DPPH free radical scavenging assay, which, while primarily an assessment of antioxidant capacity, indirectly supports the therapeutic potential of the extracts, including potential synergistic effects on antimicrobial action. Like the previous study, Rahman (2019) focused solely on bacterial strains without incorporating fungal pathogens, which remains a notable omission in the broader context of antimicrobial research  [42] In summary, the antimicrobial investigations of Goniothalamus sesquipedalis have demonstrated significant antibacterial activity through well-established methods like the well-diffusion assay. To enhance the robustness and breadth of studies on the antimicrobial activity of Goniothalamus sesquipedalis, future research could adopt several approaches. Firstly, expanding the spectrum of microbial strains tested, including a variety of gram-positive and gram-negative bacteria, along with fungal pathogens, would provide a more comprehensive assessment of the plant's antimicrobial capabilities [46]. Incorporating advanced techniques such as broth microdilution could offer more precise measurements of minimum inhibitory concentrations (MICs), enhancing the quantitative analysis of antimicrobial potency [47]. Additionally, employing molecular techniques like mass spectrometry and NMR spectroscopy could help identify and characterize the active compounds [48–50], giving researchers a deeper understanding of the mechanisms underlying the antimicrobial effects. With the compounds identified by mass spectrometry and NMR spectroscopy, molecular docking would serves as a sophisticated computational technique that enhances the understanding of the antimicrobial properties of compounds found in Goniothalamus sesquipedalis [51–55]. This method predicts how molecular ligands from the plant might interact with specific protein targets within microbial pathogens, helping to estimate their binding affinities and potential efficacy [53,55]. A higher binding affinity indicated by docking can suggest a strong and effective interaction, potentially capable of inhibiting or altering the function of the target protein, which could result in the disruption of microbial pathogenicity and survival. The insights gained from molecular docking extend beyond simple interaction predictions. They can elucidate the mechanisms through which plant-derived compounds exert their antimicrobial effects, such as competitive inhibition—where the compound prevents the natural substrate from binding to the enzyme—or allosteric inhibition, where the compound binds to an alternative site on the protein, influencing the enzyme's activity indirectly [56,57]. These interactions can be visually analyzed through docking simulations, offering a detailed view of how plant compounds fit within the active sites of microbial proteins.

Additionally, molecular docking facilitates the optimization of bioactive compounds. By understanding how these molecules interact at a molecular level with target proteins, chemists can modify and optimize their structures to enhance binding characteristics, increase selectivity, reduce toxicity, and improve overall antimicrobial efficacy [58–62]. This approach is crucial for advancing plant-based compounds from preliminary screening stages to potential clinical applications. For practical applications in docking studies, certain microbial enzymes and proteins that are critical for pathogen survival and virulence can be targeted. Examples include DNA Gyrase (Bacterial Topoisomerase II), essential for bacterial DNA replication [63–65]; ?-ketoacyl-ACP Synthase (FabB/FabF), involved in bacterial fatty acid synthesis [66–68]; Lanosterol 14?-demethylase (CYP51), crucial in fungal ergosterol biosynthesis [69,70]; and Penicillin-Binding Proteins (PBPs), key components in bacterial cell wall synthesis [71–74]. Targeting these proteins can potentially lead to the discovery of novel antimicrobial agents that are effective against resistant strains of bacteria and fungi. Moreover, synergistic studies examining the interaction of this plant's extracts with conventional antibiotics could uncover potential enhancements in efficacy, addressing issues of antibiotic resistance [75,76].

DISSATISFACTORY ASSESSMENT OF ANTIOXIDANT ACTIVITY:

The assessment of antioxidant activity in Goniothalamus sesquipedalis has been specifically addressed in the studies by Rahman (2019), employing a distinct methodology to evaluate the plant's ability to mitigate oxidative stress [42]. Rahman’s study comprehensively examined the antioxidant capabilities of Goniothalamus sesquipedalis using the DPPH assay [42]. The DPPH assay is a widely used method to measure the ability of antioxidants to scavenge free radicals, indicated by a change in color as the radical is reduced [77–80]. Rahman. found that the ethanol extract of the plant demonstrated significant free radical scavenging activity. This finding suggests that the extract contains compounds capable of donating electrons to neutralize free radicals, thus providing a measure of the plant’s potential antioxidant effects. However, The study conducted by Rahman (2019) on the antioxidant potential of Goniothalamus sesquipedalis provides is somewhat limited by the inherent nature of the DPPH assay employed. While the DPPH assay is popular for its straightforward methodology, which involves a simple colorimetric measurement of free radical scavenging activity, it only tests the capacity to neutralize one type of free radical. This specificity might lead to an incomplete assessment of the plant's overall antioxidant capabilities, as it does not account for other reactive species such as different types of oxygen or nitrogen radicals that are biologically relevant. Various studies have addressed this limitation by proposing alternative methods to overcome interference from pigments in plant extracts [81,82] considering the spectroscopic properties of substances in the reaction medium [83], and developing modified assays to accurately measure antioxidant activity without underestimation or interference from coexisting pigments [82].  Moreover, the DPPH assay's outcomes can vary with factors like the solubility of the antioxidant, reaction time, and test conditions [84–86], which might influence the reproducibility and reliability of the results. Given these limitations, the findings from this single assay should be approached with caution, as they may not fully reflect the plant's antioxidant activity in biological systems. To enhance the understanding of the antioxidant properties of Goniothalamus sesquipedalis, it is crucial to incorporate a broader range of assays in future research. For instance, the ABTS assay, which involves a similar radical scavenging mechanism but uses a different radical that is soluble in both water and organic solvents [84,87–89], could complement the DPPH results. Additionally, the Ferric Reducing Antioxidant Power (FRAP) assay, which measures the ability of antioxidants to reduce ferric ions [90,91], could provide insight into the electron donation capacity of the plant's compounds. Other important tests include the Oxygen Radical Absorbance Capacity (ORAC) assay, which is relevant for evaluating the plant's effectiveness against biologically pertinent peroxyl radicals [92,93], and metal chelation assays, which assess the ability to bind transition metals that catalyze radical formation [78,94,95]. Furthermore, conducting in vivo antioxidant tests could reveal the extract's impact on the oxidative status in biological systems, offering a more real-world appraisal of its therapeutic potential [77,96,97].

While the studies by Habiba et al. (2019), Konsam et al. (2015), and Khan et al. (2018) did not directly assess the antioxidant activity of Goniothalamus sesquipedalis through specific assays, their findings have significant implications regarding the plant's potential antioxidant properties [19,20,43]. Konsam et al. and Khan et al. identified a variety of phytochemicals, including alkaloids, flavonoids, and tannins, known for their antioxidant capabilities [98–100]. These compounds can neutralize free radicals and may contribute to reducing oxidative stress in biological systems, suggesting possible health benefits such as anti-aging, anti-inflammatory, and anticarcinogenic effects [101–107].. These collective observations call for specific antioxidant testing in future studies to fully elucidate the therapeutic potential of Goniothalamus sesquipedalis.

ANTHELMINTIC AND INSECTICIDAL ACTIVITIES:

The study by Habiba et al. (2019) focused extensively on exploring the anthelmintic and insecticidal activities of Goniothalamus sesquipedalis, revealing significant biological effects that have implications for agricultural and pharmaceutical applications [43]. The research utilized a range of extracts from the plant, each prepared using different solvents to assess their efficacy against specific pests and parasites, specifically earthworms (Pheretima posthuma) for anthelmintic activity and rice weevils (Sitophilus oryzae) for insecticidal activity [43]. In their examination of anthelmintic activity, Habiba et al. utilized a bioassay with adult earthworms to test various concentrations of multiple extracts of Goniothalamus sesquipedalis. [43] The study recorded the time to paralysis and death, noting a clear dose-dependent effectiveness, with higher concentrations leading to faster effects. Among the extracts, the ethanol extract was particularly noted for its potency, demonstrating strong anthelmintic properties by rapidly disrupting the biological functions of earthworms [43]. For insecticidal activity, the methodology involved treating rice weevils (Sitophilus oryzae) with the same range of plant extracts and observing mortality rates over 24 hours. The results showed dose-dependent lethality, with higher concentrations resulting in higher mortality rates. These findings suggest potential applications in organic farming and natural pest control, positioning the extracts as eco-friendly alternatives to synthetic insecticides.

 The study by Habiba et al. significantly contributes to the understanding of the potential uses of Goniothalamus sesquipedalis in pest and parasite control. The demonstrated anthelmintic and insecticidal activities suggest that extracts from this plant could be developed into natural remedies for controlling parasitic worms and agricultural pests. However, further research is necessary to isolate and identify the specific active compounds responsible for these effects, understand their mechanisms of action, and assess their safety and efficacy in real-world conditions. Additionally, expanding the scope of testing to include other pests and parasites could broaden the applicability of the findings.

PHYLOGENETIC EVALUATIONS:

The BioProject (NCBI Accession ID: PRJNA508895), involves multiple studies that explore the evolution and diversification of tropical rainforests at global scales. The project includes contributions from various studies, notably those by Couvreur T et al. (2019), which uses targeted enrichment of nuclear genes to understand the phylogenomics of the Annonaceae family, and by Bréé B et al. (2020), which discusses the diversification of specific African rainforest-restricted clades within the family [23,24]. These  explores the diversification of African rainforest-restricted clades within the Annonaceae family, revealing how historical biogeography and speciation events shaped their distribution and adaptation and uses targeted enrichment of nuclear genes to analyze the phylogenomics of the Annonaceae family, providing a detailed framework for understanding the evolutionary relationships and genetic lineage of species like Goniothalamus sesquipedalis[23,24]. In another study primarily aimed to enhance the understanding of phylogenetic relationships within the Annonaceae family using advanced genomic techniques, specifically focusing on the targeted enrichment of nuclear genes to obtain a more resolved and accurate phylogeny [4]. This approach targeted specific genes believed to be crucial in evolutionary developments and adaptations across various species within the family. Methodologically, the Tang et al. (2013) employed a targeted enrichment approach, selecting particular segments of nuclear DNA for sequencing, which is especially useful in phylogenetics as it allows for the comparison of many genes across multiple species, providing a comprehensive genetic overview that is more informative than traditional single-gene studies [4]. By sequencing these targeted regions, high-resolution data were gathered to construct a detailed phylogenetic tree. Within this broader study, Goniothalamus sesquipedalis was one of the species sampled for genetic data, and the sequences obtained helped place it accurately within the phylogenetic tree of the Annonaceae family [4]. The study identified several sequences from Goniothalamus sesquipedalis, specifically GenBank accession numbers KM818553, KM818612, KM818670, KM818712, KM818845, KM818929, KM818988, KM818781, and KM818744, which helped in accurately placing this species within the phylogenetic tree of the Annonaceae family [4].  Goniothalamus sesquipedalis, closely related to Goniothalamus tapis known for its anticancer and antimicrobial properties [108], and Goniothalamus macrophyllus with noted anti-inflammatory and anticancer effects [109], may similarly possess valuable bioactive compounds, indicating significant pharmaceutical potential.

COMPOUNDS ISOLATED FROM GONIOTHALAMUS SESQUIPEDALIS ELUCIDATES BIOACTIVITY:

A small number of compounds isolated from Goniothalamus sesquipedalis can be found from literature [22,25,26]. The isolated compounds from various parts of the plant highlight its diverse phytochemical profile. From the leaves and twigs, compounds such as Goniopedaline, aristololactam A-II, taliscanine, aurantiamide acetate, ?-sitosterol, and ?-d-glucoside have been isolated. These substances are known for their bioactive properties, which can include antimicrobial, anti-inflammatory, and possibly anticancer effects. Additionally, from the stem bark, a distinct compound named 6S-(5-acetoxy)-7S, 8R-epoxystyryl-5,6-dihydro-2-pyrone (5-acetoxyisogoniothalamin oxide) has been extracted. This specific compound might offer unique biological activities, contributing further to the medicinal potential of the plant.

Some of these compounds are evaluated of their pharmacological properties using ADMET 2.0 [27,28].

Table 2: Pharmacological Properties of Compounds from Goniothalamus sesquipedalis

As given in Table 2, here are some of the most interesting parts of the analysis:

LogS (Solubility):

The negative LogS values indicate low solubility in water for all compounds [110], which might challenge their formulation for oral administration unless modifications or advanced delivery methods are employed.

LogP (Lipophilicity):

Values around 3.6-3.85 suggest that these compounds are moderately lipophilic [111,112], favoring absorption across cell membranes but might also indicate a risk of accumulating in fatty tissues.

Human Intestinal Absorption (HIA):

Except for Aurantiamide acetate, which shows almost complete absorption, the other compounds have very low absorption rates, potentially limiting their effectiveness when administered orally [113,114].

Blood-Brain Barrier (BBB):

All compounds have low permeability predictions regarding the blood-brain barrier, suggesting that they are less likely to affect central nervous system targets [115,116].

Plasma Protein Binding (PPB):

High binding rates (over 90%) indicate that these compounds, once in the bloodstream, are likely to bind significantly to plasma proteins, which could reduce their free concentration available for therapeutic action but might also prolong their systemic retention [117,118]. In simple terms, while these compounds show potential due to their lipophilic nature and in the case of Aurantiamide acetate, excellent intestinal absorption, their low water solubility and high plasma protein binding pose challenges for drug development. Strategies to enhance solubility and bioavailability will be crucial in harnessing their therapeutic potential.

CONCLUSION:

The comprehensive review of Goniothalamus sesquipedalis within the context of traditional and modern pharmacology underscores its significant potential as a source of bioactive compounds. As detailed through various studies, this plant exhibits a broad spectrum of biological activities ranging from antimicrobial to analgesic properties [19,20]. The identification of specific compounds like Goniopedaline, Aristololactam A-II, and Aurantiamide acetate further validates the ethnomedicinal use of the plant, providing a scientific basis for its application in traditional medicine practices across various Asian communities [9,22]. Pharmacological evaluations, particularly those assessing ADMET properties, reveal challenges such as low solubility and high plasma protein binding, which could hinder the development of these compounds into therapeutic agents [27,28]. However, these challenges also open avenues for future research to optimize these compounds for better bioavailability. Additionally, the phylogenetic studies linking Goniothalamus sesquipedalis to other species within the Annonaceae family highlight potential comparative paths to discover and harness similar bioactive profiles [4,23,24]. Despite the promising bioactivity profiles, the lack of extensive studies on this rare species, particularly those employing advanced molecular and in vivo methodologies, suggests a significant gap in the current scientific literature. This gap not only presents an opportunity for future research but also underscores the need for a concerted effort to explore this underutilized resource more comprehensively. Integrating advanced analytical techniques, such as mass spectrometry and molecular docking, with traditional ethnobotanical knowledge could yield new insights into the therapeutic potentials of Goniothalamus sesquipedalis. In conclusion, Goniothalamus sesquipedalis represents a reservoir of medicinal potential, aligned with both historical usage and modern pharmacological standards. Its continued study not only promises to expand our understanding of its bioactive compounds but also contributes to the broader fields of ethnopharmacology and drug development, potentially leading to novel therapeutic agents that be able to take advantage of the unique properties of this relatively rare species.

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