Murraya koenigii L. Spreng.: An updated review of chemical composition, pharmacological effects, and toxicity studies

INTRODUCTION

Murraya koenigii is a tropical to subtropical plant belonging to the Rutaceae family. This plant is known as “Salam India” in Indonesia and has various regional names such as temurui (Aceh), koro keling (Semarang), sicerek (Minangkabau), and ki becetah (Sunda). In other countries, this plant is referred to as curry (English), garupillai (Malaysia), kerriebladeren (Dutch), feuilles de cari (French), curryblatter (German), fogli de cari (Italian), and hoja (Spanish) [1].

Taxonomy of plant

Kingdom: Plantae

Sub-kingdom: Tracheobionta

Superdivision: Spermatophyta

Division: Magnoliophyta

Class: Magnoliospida

Subclass: Rosidae

Order: Sapindales

Family: Rutaceae

Genus: Murraya

Species: Murraya koenigii

Murraya koenigii is a shrub or small tree, typically growing between 2.5 and 6 m in height [2]. This plant has a short stem with a diameter of 15–40 cm, which is grayish or brown, and lush foliage [3]. Its compound leaves are bipinnately, showcasing 11–21 leaflets, each measuring 2–4 cm in length, and 1–2 cm in width, emitting a distinctive aroma. The bisexual flowers are small, fragrant, and white, while the small egg-shaped fruits have a length of 1.4–1.6 cm and a diameter of 1–1.2 cm, turning purplish–black when ripe [4]. The seeds are approximately 11 mm in length, and 8 mm in diameter, with a weight of about 445 mg [5]. A visual representation of M. koenigii plant is presented in Figure 1.

Figure 1. Murraya koenigii (L.) Spreng. (a) Plant. (b) Leaves. (c) Flower. [Click here to view]

Murraya koenigii is known for its aromatic leaves used in culinary spice. The most important chemical compounds responsible for its strong distinctive aroma are p-gurjunene, p-caryophyllene, p-elemene, and O-phellandrene. This plant is also high in carbazole alkaloids such as mahanimbine, murrayanine, murrayacine, girinimbine, isomurrayazoline, mahanine, koenine, koenigine, koenidine, koenimbine [6,7], O-methylmahanine, O-methylmurrayamine, isomahanine, bismahanine, and bispyrayafoline [8]. Traditionally, this plant has been used for its stimulant, stomachic, antipyretic, analgesic, and medicinal properties in the treatment of diarrhea, dysentery, and insect bites, as well as its anti-inflammatory and antidepressant effects [9]. Topically applying a paste made from fresh leaves is known to neutralize toxins from animal bites [10].

METHODS

A comprehensive literature search for scientific studies published in electronic databases was conducted. This study reviewed more than 200 scientific papers from various international sources, including PubMed [www.ncbi.nlm.nih.gov/pubmed/], Google Scholar [https://scholar.google.com.pk/], and Scopus [www.scopus.com]. Subsequently, the studies were electronically searched from 1965 to 2023, and only 120 papers were found suitable for this review. The following keywords were used to search the databases: “Murraya koenigii,” “Chemical Composition,” “pharmacological effects,” and “toxicity.” All chemical structures were visualized using ChemDraw Ultra 18.0 software.

RESULTS AND DISCUSSION

Pharmacological effects of M. koenigii

Currently, a study of the pharmacological activities of M. koenigii indicates that its extracts and chemical components exhibit a wide range of biological activities. These activities include anti-inflammatory and analgesic effects, hemostatic coagulation, antibacterial activity, antioxidant effects, anti-tumor effects, and more. Based on this study, pharmacological effects primarily focused on alcohol, water, and methanol extracts, among others. The active compounds isolated from these extracts and their associated pharmacological effects are summarized in Figure 8. The following activities will be detailed.

Table 1. Alkaloids reported from M. koenigii. [Click here to view]

Anti-inflammatory and analgesic effects

Ethanol extract of M. koenigii leaf has shown significant anti-inflammatory and analgesic activities when tested using the carrageenan-induced paw edema method in rats [62,63], as well as methanol extracts [64], and others. Furthermore, ethanol extracts (300 and 400 mg/kg) also act as antihistamines and can stabilize mast cells [65]. Mani et al. [66] further showed that M. koenigii leaf extracts effectively relieve pain induced by intraperitoneal acetic acid and subplantar formalin injection in rats.

Methanol extracts from M. koenigii have demonstrated the ability to inhibit glutamate-induced pain, with their antinociceptive mechanisms including adenosina trifosfat-sensitive K+ channels [67]. In another study by Nalli et al. [12], compounds such as murrayakonine A, O-methylmurrayamine A, and mukolidine isolated from M. koenigii leaf and stems were found to inhibit the release of inflammatory mediators tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6. Furthermore, girinimbine exhibited anti-inflammatory activity tested on RAW 264.7 cells induced by lipopolysaccharides by reducing nitric oxide (NO) levels and proinflammatory cytokines IL-1β and TNF-α [11]. Husna et al. [68] also proved that ethanol extracts from the leaves pose anti-inflammatory and hepatoprotective activities and play a role in regenerating damaged pancreatic islets.

Antidiabetic

Regarding its antidiabetic properties, studies have shown that feeding rats M. koenigii leaf diets leads to hypoglycemic and antihyperglycemic effects [69]. Ethanol extracts of M. koenigii have also been shown to significantly reduce blood glucose levels [70], with the hypoglycemic effect attributed to their antioxidant properties and insulin-mimetic effects. In addition, M. koenigii exhibits profound antioxidant effects by reducing levels of malondialdehyde, increasing high levels of glutathione, and significantly lowering the homeostatic model assessment-insulin resistance index [71,72].

Oral administration of M. koenigii leaf water extracts has been shown to reduce blood glucose levels in diabetic rats and alloxan-induced diabetic rabbits [73–78]. Chloroform leaf extracts also exhibit antidiabetic activity at doses of 250 and 500 mg/kg body weight in alloxan-induced diabetic rats [79]. In addition, the juice of M. koenigii fruit also lowers blood glucose levels in diabetic rats [80].

Mahanimbine was isolated from M. koenigii using dry petroleum ether extract column chromatography. The antidiabetic activity was conducted on Wistar rats induced with streptozotocin using pure compound at doses of 50 and 100 mg/kg. The results showed the presence of antidiabetic and antilipidemic activities of mahanimbine [47]. In addition, koenidine showed a significant decrease in postprandial blood glucose levels with increased insulin sensitivity in type 2 diabetic rats [81].

Figure 2. Structures of alkaloids from M. koenigii (L.) Spreng. [Click here to view]

Table 2. Fenilpropanoid reported from M. koenigii. [Click here to view]

Figure 3. Structures of fenilpropanoid from M. koenigii (L.) Spreng. [Click here to view]

Table 3. Alkanes reported from M. koenigii (L.) Spreng. [Click here to view]

Figure 4. Structures of alkana from M. koenigii (L.) Spreng. [Click here to view]

In clinical trials, the administration of M. koenigii leaf powder showed a significant difference in the average fasting and postprandial blood glucose levels in diabetic patients [82]. Sampath et al. [13] demonstrated that a compound derived from M. koenigii, known as 3,3′,5,5′,8-pentamethyl-3,3′-bis(4-methylpent-3-en-1-yl)-3,3′,11,11’-tetrahydro-10,10′-bipyrano (3,2-a) carbazole exhibited in vitro inhibition activity against α-amylase and α-glucosidase, showcasing its potential as an antidiabetic agent. Furthermore, the findings showed that this compound has antidiabetic activity. Its extract exhibited an antihyperglycemic effect by improving key enzymes on carbohydrate metabolism and increased glucose transporter-4 expression against hyperglycemic rats [83]. A 1-month trial of supplementing with 12 g of M. koenigii leaf powder (providing 2.5 g of fiber) was conducted in 30 patients with noninsulin-dependent diabetes mellitus. The findings revealed a temporary decrease in fasting and postprandial blood sugar levels after 15 days, with no significant alterations observed in glycosylated protein levels, glycosylated low-density lipoprotein cholesterol fraction, serum lipids, lipoprotein cholesterol levels, uronic acid, and total amino acids throughout the supplementation period, either at 15 or 30 days [84].

Anticancer effect

Regarding its anticancer properties, M. koenigii leaf has shown potential as an anticancer agent against HeLa cells [85], and colorectal cancer [86]. In addition, the methanol extract of M. koenigii has been reported to have the ability to reduce proliferation in breast cancer cells [87,88]. Alkaloids extracted from the leaves have also been proven to have cytotoxic activity against breast cancer cells with an inhibition concentration (IC₅₀) of 14.4 μg/ml [89].

Ito et al. [90] demonstrated that mahanine, pyrafoline-D, and murrafoline-I exhibited significant cytotoxic activity against HL-60 cells. In addition, girinimbine, a carbazole alkaloid isolated from M. koenigii, showed anticancer activity against human hepatocellular carcinoma and lung cancer [48]. Microtetrazolium assays revealed that girinimbine induced cell death with IC₅₀ 19.01 μM [91]. Koenimbin, another compound isolated from M. koenigii exhibited activity in inhibiting MCF7 breast cancer cells [92,93]. Moreover, murrayazoline and O-methylmurrayamine A, obtained from the isolation of these plant leaves showed activity against colorectal cancer through down-regulation of the Akt/mTOR survival pathway and activation of the intrinsic pathway of apoptosis [94]. Mahanimbine, also isolated from M. koenigii leaf, has been shown to inhibit P-glycoprotein involved in lung cancer chemoresistance [14].

Chemoprotective activity

The methanol extract of M. koenigii leaf, administered as a single dose of 100 mg/kg before intraperitoneal injection of 50 mg/kg cyclophosphamide in albino rats, exhibited a protective effect by reducing cyclophosphamide-induced chromosomal damage and enhanced bone protection [95].

Antioxidant effect

In terms of its antioxidant properties, a study by Tachibana et al. [21] indicated that compounds such as mahanimbine and koenigine, derived from leaves, possess antioxidant activity. Antioxidant activity was assessed using the β-carotene-linoleic acid method. Among the various extracts, M. koenigii oleoresin exhibited a maximum activity of 83.2% at 100 ppm, while methanol and water extracts showed activities of 16.7% and 11.3%, respectively. Subsequently, butylhydroxyanisole (a synthetic antioxidant) exhibited 90.2% activity at the same concentration [96]. The ethanol extract obtained from the leaves demonstrated activity against free radical scavenging as tested using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and NO methods [97]. The ethanol extract also showed high antioxidant activity with an inhibition value of 63.54% in the DPPH assay [98].

Table 4. Terpenoid reported from M. koenigii. [Click here to view]

Figure 5. Structures of terpenoids from M. koenigii (L.) Spreng. [Click here to view]

Wound healing effect

Murraya koenigii leaf has been found to possess wound-healing activity by reducing epithelialization and supporting collagen synthesis [7]. In addition, the ethanol extract of its leaves exhibited wound-healing activity in excision and incision wound models in male rats [99].

Antipyretic activity

Regarding its antipyretic effects, this study has shown that the ethanol extract derived from M. koenigii leaves has antipyretic activity. This was demonstrated in fever-induced rats using intraperitoneal administration of brewer’s yeast [100] and pyrexia induction methods comparable to paracetamol [101]. Furthermore, the ethanol extract from the leaves also exhibited significant antipyretic activity with the PG1-induced hyperpyrexia method in rabbits [102].

Table 5. Flavonoid reported from M. koenigii (L.) Spreng. [Click here to view]

Immunomodulatory activity

The water extract of M. koenigii leaf possesses both specific and nonspecific immunomodulatory activities [103]. The immunomodulatory and anti-inflammatory activities are characterized by the expression of ILs-2, 4, 10, and TNF-α [104].

Hepatoprotective activity

In terms of hepat`oprotective activity, experimental studies have demonstrated that M. koenigii extract offers protection against chronic liver disorders [104]. The hepatoprotective compounds identified in this context include carbazole alkaloids such as mahanimbine, girinimbine, isomahanimbine, murrayazoline, and mahanine [15].

Long-term alcohol consumption is a prevalent and significant factor leading to liver failure and death. Due to the lack of reliable hepatoprotective drugs, the situation becomes more complex. This encourages patients to choose and turn to complementary and alternative medicines to address and handle hepatic complications. The tannins and carbazole alkaloids found in the aqueous extracts showed impressive hepatoprotective effects against ethanol-induced liver toxicity, comparable to the standard drug L-ornithine L-aspartate [105].

Anthelmintic activity

The leaf of M. koenigii has shown anthelmintic effects on the eggs and larvae of Haemonchus contortus [106,107]. In addition, ethanol and water extracts of the leaves exhibit anthelmintic effects comparable to the standard drug piperazine against Pheretima posthuma [108]. Ethanol and water extracts from M. koenigii roots also exhibit anthelmintic activity against Eudrilllus eugeniae [109].

Antimicrobial activity

Regarding its antimicrobial activity, various extracts from M. koenigii have been reported to exhibit antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and fungi, assessed through in vitro methods such as agar well diffusion and disk diffusion. Hexane, methanol, and chloroform extracts from M. koenigii roots exhibit antimicrobial activity against Bacillus subtilis, Escherichia coli, Staphylococcus aureus, and Salmonella typhi, as well as fungi such as Aspergillus niger, Candida albicans, and Trichophyton rubrum [110]. The ethanol leaf extract of M. koenigii shows antibacterial activity against Staphylococcus, E. coli, Streptococcus, Proteus, Klebsiella pneumoniae, and Pseudomonas aeruginosa with clear inhibition zones comparable to antibiotics such as amikacin and gentamicin, although not effective against K. pneumoniae and P. aeruginosa [111].

Figure 6. Structures of flavonoid from M. koenigii (L.) Spreng. [Click here to view]

Derivatives of benzoisofuranone and carbazole alkaloids obtained from the stem bark of M. koenigii also possess antibacterial and antifungal activities [9]. In addition, the ethanol leaf extract exhibits antifungal activity against Trichophyton mentagrophytes and Microsporum gypseum [112].

Antiulcer activity

The water extract of the leaves at doses of 250 and 400 mg/kg inhibits gastric lesions induced by nonsteroidal anti-inflammatory drugs and pylorus ligation models [113].

Table 6. Other compounds reported from M. koenigii. [Click here to view]

Antidiarrheal activity

The water extract of the leaves exhibits antidiarrheal activity in models of castor oil-induced diarrhea, charcoal meal test, and prostaglandinE2-induced diarrhea [114,115]. Subsequently, koenimbine obtained from M. koenigii seeds exhibits antidiarrheal activity in castor oil-induced diarrhea in rats [37].

Antiobese activity

The ethanol leaf extract of M. koenigii, administered orally to male Wistar rats for 30 days, effectively reduces body weight, cholesterol, triglycerides, and controls glycemic levels [116].

Neuroprotektif activity

The ethanol leaf extract of M. koenigii inhibits brain aging in diabetic rats [117]. The extract also improves memory in rats with chronic partial global cerebral ischemia [118]. In addition, mahanimbine exhibited potential neuroprotective properties against lipopolysaccharide-induced nerve inflammation [119].

Antitrichomonal activity

Carbazole alkaloids and their derivatives from the leaves have activity against Trichomonas gallinae. Girinimbin and girinimbilol are the most active compounds with IC₅₀ values of 1.08 and 1.20 mg/ml [120].

Toxicity test

The methanol extract of M. koenigii leaf exhibited moderate toxicity in rats, with an lethal dose (LD₅₀) value of 316.23 mg/kg body weight, causing liver inflammation at higher doses [121]. However, no signs of death or morbidity were observed in male or female rats given ethanol leaf extract (300 and 500 mg/kg) for 28 days. At a dose of 900 mg/kg, there were no deaths, but congestion, hemorrhage, and lymphocyte infiltration were noted [122]. Other studies have shown that leaf powder and methanolic leaf extract are safe up to 9,000 mg/kg doses in rats [123]. Another study found no signs of death or toxicity at an LD₅₀ value of 200 mg/kg/day for methanol extract of M. koenigii [124].

Figure 7. Structures of another compound from M. koenigii (L.) Spreng. [Click here to view]

Figure 8. Relationship between chemical compounds from M. koenigii (L.) Spreng and their pharmacological effects. [Click here to view]

Ethanol leaf extract at doses of 300 and 500 mg/kg for 28 days did not result in death or morbidity in male or female rats. At a dose of 900 mg/kg, it did not cause death but led to bleeding and lymphocyte infiltration. At a dose of 900 mg/kg, it did not cause death but led to bleeding and lymphocyte infiltration. This study concluded that consumption at a dose of 500 mg/kg is safe and does not cause structural organ damage [120]. Subsequently, rats given a magazine-enriched fraction at a single dose of 5,000 mg/kg body weight, 300–1,500 mg/kg body weight per day for 14 days, and 300 mg/kg body weight for 180 days showed no toxicity, mortality, or significant behavioral changes [124]. Azzubaidi et al. [123] stated that the LD₅₀ of M. koenigii leaf extract is 200 mg/kg/day, and the safest extract dose should not exceed 50 mg/kg/day.

CONCLUSION

In conclusion, M. koenigii has been extensively studied, thereby contributing to the understanding of secondary metabolites and their biological activities in nature. Furthermore, alkaloids were observed to have been the dominant compounds from M. koenigii, followed by terpenoid and fenil propanoid. The literature reports showed that the plant exhibited various biological activities, such as anti-inflammatory, cytotoxic, antidiabetic, and antimicrobial activity. This study showed that most pharmacological activity studies are still limited to in-vitro and in-vivo screenings, with mechanisms of action, bioavailability, and pharmacokinetics not yet explored. Subsequently, further studies should focus on the isolation of phytochemical compounds guided by bioassays, formulation, and drug delivery methods, serving as the basis for drug discovery. This review focuses on scientific studies of the pharmacological effects of M. koenigii.

ACKNOWLEDGMENTS

We would like to thank wholeheartedly Hibah Rekognisi Tugas Akhir of the Universitas Gadjah Mada (Grant number: 5075/UNI.P.II/Dit-Lit/PT.0101/2023) for supporting and providing the research facility for this work.

AUTHOR CONTRIBUTIONS

YDF has equally contributed to conceptualization and writing. NF, and AN reviewed and edited. All authors have read and agreed to the published version of the manuscript.

CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY

All data generated and analyzed are included in this research article.

PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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