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A Review on the Potency of Melaleuca leucadendron Leaves Solid Waste in Wood Preservation and Its In Silico Prediction upon Biological Activities

A Review on the Potency of Melaleuca leucadendron Leaves Solid Waste in Wood Preservation and Its... Hindawi International Journal of Forestry Research Volume 2020, Article ID 8885259, 13 pages https://doi.org/10.1155/2020/8885259 Review Article A Review on the Potency of Melaleuca leucadendron Leaves Solid Waste in Wood Preservation and Its In Silico Prediction upon Biological Activities 1 2 1 Christine Patramurti , Radjali Amin , Christofori M. R. R. Nastiti , and Maywan Hariono Faculty of Pharmacy, Sanata Dharma University, Sleman, Daerah Istimewa, Yogyakarta 55282, Indonesia Post-Graduate School, Yogyakarta Institute of Technology, Bantul, Daerah Istimewa, Yogyakarta 55198, Indonesia Correspondence should be addressed to Maywan Hariono; mhariono@usd.ac.id Received 29 September 2020; Revised 29 October 2020; Accepted 3 November 2020; Published 17 November 2020 Academic Editor: Ahmad A. Omar Copyright © 2020 Christine Patramurti et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (e essential oils from cajuput leaves (Melaleuca leucadendron) have been well-known and applied, especially in healthcare management. However, the utilization of the leaves solid waste has not been explored and reported in detail. In this review, we elaborate on the cajuput leaves starting from the plant description and leaf morphology, chemical composition, biological activities, wood decomposing organism, and an in silico prediction upon its molecular mechanism. Based on the in silico prediction, compounds such as guaiol, lupene, and 1, 8-cineole have the potential to be antifungal and insecticide that associates with the cajuput potency as a wood preservative agent. in West Java, the waste production was up to 8.3 million tons 1. Introduction per year [3]. It is only about 14% of waste was estimated to be (e leaves and small branches distillation process of cajuput directly utilized by the cajuput distillation factory [4]. (Melaleuca leucadendron (L.) L.) produces essential oils with (e research reported that solid cajuput waste can be eucalyptol (cineole) as the main chemical substance used as activated charcoal [5]. (e waste can be further (50–65%) [1]. Eucalyptol (1, 3, 3-trimethyl-2-oxabicyclo processed as the biopellet and briquette charcoals [6]. (e [2.2.2]octane) is classified as the oxygenized monoterpene calorie value of cajuput briquette charcoal is much higher hydrocarbon group. (is compound plays an important role than the common briquette charcoals [2] that can reach up in its antibacterial activity against Gram-positive and Gram- to 1.5 times magnitude [7, 8]. (is solid waste also contains negative bacteria. (e biological activities were also reported volatile gases with a quantity of up to 47–68% [5, 7]. (is waste was also utilized as fuel such as in a steam boiler [9] against fungus and insects which could be due to that one of the major eucalyptol compounds borne a chemical structure and as a food substitute for cow cattle on the farm [10]. A as 1, 8-cineole (Figure 1) [1]. study by Rahmawati et al. reported that cajuput waste can be Besides the essential oils, the distillation process of processed as an organic soil fertilizer [4]; however, the cajuput produces solid residue (waste), i.e., the cajuput process of decomposition was slow triggering several studies leaves mixed with small and big branches. (e leaves solid to investigate the environmental factors accelerating this waste still contains the essential oil which composes waste decomposition process [11]. Interestingly, no study chemicals similar to its fresh leaves when they were distilled. has been carried out to investigate the chemical substances In Maluku (Indonesia), the waste was produced in ap- in cajuput solid waste which might slow down the de- proximately 51 million tons per year up to 2013 [2], whereas composition process. 2 International Journal of Forestry Research 3. Chemical Compositions H C CH Most of the chemical composition of cajuput was found H C from its leaves. (e (E, S)-nerolidol and related alcohols such as farnesol and geraniol were found from the leaves of Melaleuca leucadendron which was used in feeding deterrent of the gypsy moth larvae [24]. (e high content of two Figure 1: (e chemical structure of 1, 8-cineole. phenylpropanoid chemotypes was furthered isolated from the Melaleuca leaves, which were methyl eugenol (99%) and methyl isoeugenol (88%; both in Z and E configuration). On (e 1, 8-cineole which is one of the main components of the other hand, small amounts of trans-β-ocimene and eucalyptol [1] is predicted as the chemical which inhibits the linalool were also detected [25]. (e chemical structure of decomposition due to its activities as an antibacterial, an- eugenol, isoeugenol, trans-β-ocimene, and linalool is illus- tifungal, and insecticide agent. To date, no study identifies trated in Figures 3(a)–3(d), respectively. the concentration of 1, 8-cineole in the cajuput leaves solid By distillation, the fresh leaves of cajuput were producing waste and the probability of other compounds supporting essential oils containing a-pinene, β-pinene, β-myrcene, the role in the decomposition inhibition. It is estimated that limonene, c-terpinene, 1, 8-cineole, p-cymene, terpinolene, if these chemicals can be well isolated, they may be further benzaldehyde, linalool, trans-pinene hydrate, terpin-4-ol, utilized in the wooden furniture preservation, thereby in- c-terpineol, α-terpineol, 1-tetradecene, ledol, valencene, creasing the economic values of the solid cajuput waste. (is eugenol, α-eudesmol, and β-eudesmol as the main con- review article focuses on the progress studying the chemical stituents (64%) [15]. (e similar distillation process was constituent identification and the biological activities of carried out to hydrodistill essential oil from cajuput leaves cajuput leaves. Subsequently, the in silico prediction on how observing the other major constituents such as β-eudesmol the chemicals in cajuput leaves solid waste interact with the (15.8%), α-eudesmol (11.3%), viridiflorol (8.8%), and guaiol protein expressed by wood decomposing microorganisms is (9.0%) (Figures 3(e)–3(h), respectively) [26]. also reviewed. A study by Yoshida et al. on the chemical identification of cajuput dried fruits indicated a new hydrolyzable tannin and other polyphenols as the secondary metabolite being 2. Plants Description and Leaf Morphology deposited. (ey were 1, 2-di-O-galloyl-3-O-digalloyl-4, 6-O- (S)-hexahydroxydiphenoyl-3-Iβ-glucose (Figure 4(a)) and (e genus of Melaleuca (Myrtaceae family) covers at least 230 species in the world, mostly found in Tasmania (Aus- nine known hydrolyzable tannins. Commonly known stil- bene glycoside and triterpene were also identified [27]. tralia), Indonesia, Papua New Guinea, Tropical America, A comprehensive study was successfully performed to and South Asia [12, 13]. (e main genera utilized for the production of commercial essential oils and aromatherapy identify further triterpene from the leaves and heartwood of cajuput. A novel lupene-type nortriterpene (28-norlup-20(29)- are Melaleuca alternifolia (Maiden and Betche) Cheel (tea tree oil), Melaleuca cajuputi Powell (cajuput oil), and ene-3β, 17β-diol) as well as 13 other known compounds were characterized. (e other 13 compounds were (2E, 6E)-farnesol, Melaleuca quinquenervia (Cav.) S. T. Blake (niaouli oil). Other well-known genera are Melaleuca leucadendron, phytol, squalene, alloaromadendrene, ledene, palustrol, vir- idiflorol, ledol, betulinaldehyde, betulinic acid, 3β-acetyl-lup- Melaleuca viridiflora, Melaleuca acacioides, Melaleuca alsophila, Melaleuca bracteata, and Melaleuca argentea 20(29)-en-28-oic acid, 3-oxolup-20(29)-en-28-oic acid, and platanic acid [28]. Further novel triterpenes were characterized, [14, 15]. (e trees of Melaleuca leucadendron are approxi- mately 40m high, which is grown in northern Australia, the i.e., 3β-cis-coumaroyloxy-2α-hydroxyursa-12, 20(30)-dien-28- oicacid, and cis- and trans-3β-caffeoyloxy-2α-hydroxyurs-12- south coast of New-Guinea, and the east coasts of Indonesia en-28-oic acids from the leaves as well [29]. Research also [12]. (e morphology of Melaleuca leucadendron leaves is a blade narrowly ovate, very narrowly ovate, rarely narrowly successfully identified three new triterpenes from the heart- wood of cajuput [30]. (ey are 23-trans-p-coumaroyloxy-2α, elliptic, or very narrowly elliptic (often falcate to subfalcate). (e leaves are 3.5–16 times longer compared to the width; 3β-dihydroxyolean-12-en-28-oic acid, 3β-trans-caffeoyloxy- 2α,23-dihydroxyolean-12-en-28-oic acid, and its isomer 3p- petals are with elliptic oil glands (occasionally long elliptic glands form an apparently linear gland) [16]. (e tree of cis-caffeoyloxy-2α, 23-dihydroxyolean-12-en-28-oic acid [31]. (e general structure of lupene is shown in Figure 4(b). cajuput and its leaves are presented in Figure 2. A number of protocols have been applied to standardize the components Having isolated from the heartwood, four new tri- terpenes were characterized including eupha-7, 24-diene-3α, of the leaves and the extract including phytochemical screening, thin layer chromatography profile, organoleptic 22α-diol, 20-taraxastene-3R, 28-diol, 3R-hydroxy-13(18)- oleanene-27, 28-dioic acid, and 3R, 27-dihydroxy-28, 20α- evaluation, histological and microscopic techniques of taraxastanolide. Besides, Lee also identified four novel leaves, powder microscopic, physicochemical parameters, quantitative microscopy, and evaluation of volatile oil β-triketone flavanones from the leaves. (e compounds were then named as leucadenone A to leucadenone D [32]. [17–23]. International Journal of Forestry Research 3 (a) (b) Figure 2: (e habitus of (a) tree of cajuput and (b) its leaves. (e photos were taken in Sendang Mole, Playen, Gunung Kidul, Daerah Istimewa Yogyakarta. CH CH CH CH 2 3 2 3 OH CH HO HO CH H C H C 3 3 H C CH 3 3 H C CH 3 3 (a) (b) (c) (d) OH OH H C H H C 3 CH H C CH 3 HO 3 3 C CH H C 3 3 H C CH H C 3 H C H C 3 CH H C H C 2 3 H C H C OH CH (e) (f) (g) (h) Figure 3: (e chemical structure of (a) eugenol, (b) isoeugenol, (c) trans-β-ocimene, (d) linalool (e) β-eudesmol, (f) α-eudesmol, (g) viridiflorol, and (h) guaiol which are benefit for the antibacterial effect and are the components of hydrodistilled essential oil from cajuput leaves. 4 International Journal of Forestry Research HO HO CH OH O H C HO HO HO OH HO H C CH 3 3 CH HO H C 3 CH O O H C HO 3 CH CH OH HO (a) (b) Figure 4: (e chemical structure of (a) 1, 2-di-O-galloyl-3-O-digalloyl-4, 6-O-(S)-hexahydroxydiphenoyl-3-Iβ-glucose, the chemical composition of cajuput fruits, and (b) the general structure of lupene which are the chemical composition of the leaves. Table 1: Identification and quantification of the compounds in cajuput (Melaleuca leucadendron) (reported in 2011–2020). No. Compounds Part % or mg References 1 α-Pinene Leaves 0.22–0.68 [33] 2 α-(ujene Leaves 1.29–4.16 [33] 3 β-Pinene Leaves 0.79–2.90 [33] 4 β-Myrcene Leaves 0.31–0.95 [33] 5 Carene Leaves 0.29–1.18 [33] 6 D (+)-limonene Leaves 4.45–8.85 [33] 7 c-Terpinene Leaves 1.82–6.72 [33] 8 Terpinolene Leaves 0.67–3.62 [33] 9 1,8-Cineole Leaves 44–60 [33] 10 Linalool Leaves 0.00–0.42 [33] 11 Terpinene-4-ol Leaves 0.63–0.97 [33] 12 Ocimenol Leaves 0.09–0.20 [33] 13 α-Terpineol Leaves 5.93–12.45 [33] 14 c-Terpineol Leaves 0.36–2.06 [33] 15 Cedrene Leaves 0.00–0.61 [33] 16 β-Caryophyllene Leaves 3.78–7.64 [33] 17 Humulene Leaves 0.53–0.88 [33] 18 β-Eudesmene Leaves 0.98–3.51 [33] 19 Patchoulene Leaves 0.82–4.37 [33] 20 Germacrene D Leaves 0.17–0.60 [33] 21 Aromadendren Leaves 0.00–0.27 [33] 22 Globulol Leaves 2.70–3.60 [33] 23 Viridiflorol Leaves 0.00–0.36 [33] 24 Eugenol Leaves 2.68–4.85 [33] 25 2-Pentanone Leaves 5.0mg [33] 26 Melachromone Leaves 2.4mg [34] 27 Parietin Leaves 33.2mg [34] 28 5-Hydroxy-7-methoxy-2, 6, 8-trimethylchromone Leaves 11.7mg [34] 29 Eugenitin Leaves 10.2mg [34] 30 2, 5-Dihydroxy-7-methoxy-2, 6-dimethylchromanone Leaves [34] 31 2, 5-Dihydroxy-7-methoxy-2, 8-dimethylchromanone Leaves 2.4mg [34] 32 Noreugenin Leaves 8.3mg [34] 33 5, 7-Dihydroxy-2, 6, 8-trimethylchromone Leaves 4.8mg [34] 34 Methyl 2-acetyl-3, 5-dihydroxyphenylacetate Leaves 14.4mg [34] 35 Quercitrin Leaves 3.0mg [34] 36 β-Sitosterol Leaves 8.0mg [34] 37 5-Hydroxy-7, 40-dimethoxy-6, 8-dimethylflavone Leaves 12mg [34] 38 3, 3′, 4-Tri-O-methylellagic acid Leaves 0.04 [34] 39 Camphene Leaves 0.14 [35] International Journal of Forestry Research 5 Table 1: Continued. No. Compounds Part % or mg References 40 L-limonene Leaves 0.04 [35] 41 Rose oxide Leaves 0.13 [35] 42 Isopulegol Leaves 0.24 [35] 43 Neral Leaves 0.13 [35] 44 Geraniol Leaves 0.31 [35] 45 Geranial Leaves 0.14 [35] 46 A-terpenyl acetate Leaves 0.23 [35] 47 Δ-Elemene Leaves 0.37 [35] 48 α-Ylangene Leaves 0.36 [35] 49 α-Cubebene Leaves 1.01 [35] 50 β-Elemene Leaves 0.16 [35] 51 α-Gurjunene Leaves 0.55 [35] 52 Linalyl acetate Twigs 0.11 [36, 37] 53 Bornyl acetate Leaves 0.60 [36, 37] 54 β-Bourbonene Flowers 2.67 [36, 37] 54 (E)-β-Farnesene Flowers 0.10 [36, 37] 55 (Z)-Nerolidol Twigs 90.85 [36, 37] 56 (E)-Nerolidol Leaves 0.20 [36, 37] 57 Epi-α-cadinol Leaves 0.79 [36, 37] 58 β-Bisabolol Flowers 0.25 [36, 37] 59 (Z)-Nerolidyl acetate Twigs 0.25 [36, 37] 60 Palustrol Leaves 1.86 [36, 37] 61 Ledol Leaves 0.87 [36, 37] 62 Bulnesol Leaves 0.21 [36, 37] 63 Alloaromadendrene Leaves NR [36, 37] 64 Melaleucadines A Branches and leaves NR [38] 65 Melaleucadines B Branches and leaves 0.8 [38] 66 3-Allyl-2-methoxyphenol Leaves 0.8 [39] 67 (E)-Methyl cinnamate Leaves 95.4 [39] 68 Eugenol methyl ether Leaves NR [39] 69 (E)-3, 7-Dimethylocta-2, 6-dienal Leaves NR [40] 70 1, 1, 4, 7-Tetramethyl-1a, 2, 3, 4, 4a, 5, 6, 7b-octahydro- Leaves NR [40] 71 1H-cyclopropa[e]azulene Fruits NR [41] 72 (+)-Leumelaleucol A Fruits NR [41] 73 (−)-Leumelaleucol A Fruits NR [41] 74 Leumelaleucol B Fruits NR [41] 75 Leumelaleucol C Fruits NR [41] 76 Leumelaleucol D Fruits NR [41] 77 Leumelaleucol E Fruits NR [41] 78 Leumelaleucol F Fruits NR [41] 79 Leumelaleucol G Fruits NR [41] 80 Leumelaleucol H Fruits NR [41] 81 Leumelaleucol I Fruits NR [41] 82 Leumelaleucol J Fruits NR [41] NR, not reported. (e investigation of the chemical component in the 4.1. Antibacterial. Cajuput oil, which was hydrodistilled from the leaves, was tested against the methicillin-resistant cajuput has been highly developed in a decade. Novel and known compounds were reported enriching the database of Staphylococcus aureus (MRSA) colony [42]. (e minimum compounds from cajuput (Table 1), which were potential to bactericidal concentration (MBC) and the minimum inhi- be developed as medicine, cosmetics, aromatherapy, and bition concentration (MIC) were found to be 0.2% and 0.4%, fiber technology. respectively. (is suggested that the leaves oil was able to inhibit the resistant bacteria growth in very low concen- trations. (is finding could be the potential to overcome 4. Biological Activities bacterial resistance which has currently become an urgent public health issue. Furthermore, the antibacterial test (e preservative effect of cajuput leaves was introduced due to its chemical composition to eradicate microorganisms. Bio- against MRSA was also carried out on the ethanol extract of cajuput leaves. Maceration was used to extract the bacte- logical activities of cajuput against some microbes including ricidal constituents from the leaves, and the extract was bacteria, fungi, virus, and insects are summarized below. 6 International Journal of Forestry Research tested onto the bacteria using a good well diffusion method. subject of the study for sure. A study by Farag et al. on HSV- (e results demonstrated that ethanol extract was able to 1 was also conducted to evaluate the antiviral activity of the fresh leaves oil of cajuput. (is supported the previous inhibit the growth of bacteria. (e concentrations of 50%, 60%, 70%, 80%, 90%, and 100% showed an inhibition zone of finding that cajuput was able to inhibit HSV-1 which in- 17.2mm, 18.1mm, 19.1mm, 19.4mm, 19.7mm, and fected African green monkey kidney cells (Vero cell) with 20.1mm, respectively [43]. (e ethanol extract of cajuput oil 92% of inhibition [15]. was also previously inhibiting Escherichia coli bacterial growth with an MIC of 64 µg/mL [44]. 4.4. Repellent Activity. Cajuput leaf oil demonstrated re- Cajuput essential oil from leaves demonstrated appre- pellent activities against Aedes (43.2%), Anopheles (100%), ciable activity against Enterobacter aerogenes with inhibition and Culex mosquitoes (100%) during eight hours of mos- zone 13.7–16.2mm [39]. Enterobacter aerogenes is the quito exposure [56]. When the oil was tested into the larvae Gram-negative bacteria of the Enterobacteriaceae family of Aedes, it showed the larvicidal activity up to 3.3% at a causing bacterial infection in the wound and the respiratory concentration of 50ppm [57]. A similar study was con- as well as the urinary tract [45]. ducted by Noosidum et al. confirming the repellent activity of the oil against female Aedes aegypti mosquitoes. A high 4.2. Antifungal. (e antifungal activity of the cajuput leaf escape rate of the mosquitoes was observed for up to 24 essential oils had been determined against Fusarium hours [58]. oxysporum, 7anatephorus cucumeris, and Rhizopus ory- Further insect repellent activities of cajuput leaf oils against the vector of dengue and filariasis were reported zae [46]. (e results showed that the oils were active against F. oxysporum with IC 0.01–0.11 mg/mL and [59, 60]. (e oil was showing 97.5% repellency when it was exposed to Lasioderma serricorne, which was a serious pest against 7anatephorus cucumeris with IC 0.52–4.20 mg/ mL, but less active against R. oryzae as it only showed of tobacco leaves cigarettes, cocoa beans, cereals, oilseeds, IC of 1.35–7.61 mg/mL. Fusarium oxysporum is a soil- pulses, spices, and dried fruits [61]. Another study of the borne pathogen bacteria that cause vascular wilts in repellency effect of cajuput leaf oils against Sitotroga cere- several plants [47]. 7anatephorus cucumeris which is alella was also reported. (e oil repelled up to 61% after the classified as basidiomycetes also causes plant diseases to photo natural period of Sitotroga cerealella, a Lepidoptera numerous agricultural and horticultural plants worldwide insect which causes an unpleasant smell of grains [62]. [48]. Rhizopus oryzae is a parasitic fungus that penetrates Cajuput leaf oils were also reported to have repellent ac- in the citrus fruit tissue through microwounds and tivities against Plutella xylostella, the most important pest in cabbage [63]. bruises [49]. Along with the above studies, the antifungal assay of cajuput leaf oils was also determined against Fomitopsis 4.5. Wood Decomposing Organisms. Organic material de- palustris, Tinea versicolor, and Chaetomium globosum. composition is carried out by microbes or mesofauna. (is According to Rini et al., the cajuput leaf oils demonstrated process breaks down the materials into basic elements such antifungal activities with IC 0.12–3.16mg/mL, as N, P, K, Mg, and Ca, which are important for soil nu- 0.01–0.06mg/mL, and 0, 06–0.15mg/mL for Fomitopsis trients [64]. (e microbes or mesofauna are often utilized as palustris, Tinea versicolor, and Chaetomium globosum, re- wood decomposers especially for the lignin and cellulose spectively [50]. F. palustris enzymatically breaks down the matters [65]. (ese decomposers are divided into primary cellulose of wood and leads to the plant disease namely and secondary decomposers. brown rot [51], whereas Chaetomium globosum is an en- (e primary decomposer is a mesofauna such as Col- dophytic fungus assisting the cellulose decomposition of lembola and Acarina which converts large particles into plant cells [52]. T. versicolor which is known as a turkey tail micronized sizes [66]. A wood decomposition process is also mushroom exhibits anticancer activities due to the poly- generally related to macrowood decomposers, which could saccharide constituents [53]. Candidiasis is a fungal infec- be insects and termites [67]. When the trees are logged tion which commonly occurs in female, particularly in the down, the decomposers start to attack the wood, especially to female reproductive organ. (e cajuput leaf oils potentially that sapwood which is rich in cellulose and carbohydrate. eradicated the Candida albicans with MIC 62.5 µg/mL which (e moist environment further supports the existence of the is comparable to ketoconazole, the well-known synthetic wood decomposers in the trees [68]. Hollowish trees in- drug used to treat candidiasis [54]. cluding rubber (Hevea brasiliensis), palm oil (Elaeis sp.), walnuts (Canarium vulgare), and fire tree (Delonix regia) are 4.3. Antivirus. (e potential antiviral activity of cajuput commonly attacked by ground/subterranean termites (ge- aqueous and methanol extracts were investigated against nus of Coptotermes) [69]. herpes simplex virus-1 (HSV-1) [55]. (e aqueous extract (e wood decomposition process quickly occurs once demonstrated a 55.6% plaque reduction activity. Interest- the trees died or fallen down. (is is because neither defense nor a tree recovery is leading to the direct contact between ingly, at the same concentration (100 µg/mL), the methanol extract exhibited a 100% plaque reduction defining the the dead trees with the ground rich of decomposers. (is attack is also performed by the genus of Coptotermes due to antiviral effect of such a plant against HSV-1. (is poten- tially reduced the mouse skin lesions and the mortality of the the chemical substance such as eugenol which attracts the International Journal of Forestry Research 7 expressed by Chaetomium sp. [86], whereas the laccase and termites to come over the trees [70]. Moreover, a derivative of eugenol, i.e., methyl eugenol (C H O ) has a function to peroxidase enzyme are produced by the genus of Trametes 12 24 8 [87]. stimulate the olfactory sensory organ in termites [71]. In conjunction with this, the termites have been successfully identified as a living wood attacker to cajuput which is the 4.6. In silico Prediction of the Antidecomposing Effect of genus of Odontotermes [72]. Focusing on the cajuput tree, the Macrotermes gilvus termites attack is unavoidable even Cajuput. In silico method can be potentially used to study the activity of chemical substances in cajuput oil regarding though the trees are still growing [73], especially to those of roots as well as the branches [74]. the inhibition effect to the decomposing microbial enzymes. Interaction between the 3D structure of the enzyme and the Muslich and Rulliaty examined the durability of the molecule structure of the chemical of interest can be well processed wood of cajuput from three types of decomposer’s investigated by using computational methods [88, 89]. One attack, i.e., dried ground termites (Cryptotermes cyn- of the methods is molecular docking, carried out by pre- ocephalus Light), common ground termites (Coptotermes dicting the free energy of binding as well as its conformation curvignathus Holmgren), and marine wood termites con- between micromolecule (chemical) and macromolecule clude that cajuput is resistant toward the attack of Copto- termes curvignathus but is vulnerable toward other (enzyme) [90]. Once the chemical of the oil interacts with an enzyme (by giving a negative value in the binding energy decomposers [75]. (is protective effect might be due to the chemical constituent such as cineole, melaleucin, and ter- along with its stable conformation), this conformation blocked the enzyme catalytic function in the decomposition pineol [76]. (e secondary decomposers are mostly in the form of process. (e 3D structure of the enzyme is collected from a fungi, including Trichoderma reesei, Trichoderma harzia- protein data bank (http://www.rcsb.org), which is a form of num, Trichoderma koningii, Phanerochaete chrysosporium, cryopurified enzyme crystal [91, 92]. (e crystal is then Cellulomonas, Pseudomonas, 7ermospora, Aspergillus photographed in a three-dimensional form using an X-ray Niger, Aspergillus terreus, Penicillium, and Streptomyces [77]. crystallography method. (e docking software will be fur- According to Eriksson et al., fungus is the most active de- ther used to predict the activity of such enzyme including composer which immediately converts organic materials into simpler organic elements [78]. Suprapti and Djarwanto their inhibition by using this 3D crystal. (is technique is very popular in the drug discovery process through enzyme successfully identified some fungi attacked to cajuput in- cluding Pycnoporus sanguineus, Polyporus, Trametes, inhibition that blocks pathogenic diseases [93]. In this section, we predicted the capability of some major Schizophyllum commune, Chaetomium globosum, Mar- asmius, and Dacryopinax spathularia. Pycnoporus sangui- chemicals in cajuput to interact with cellobiohydrolase from Chaetomium thermophilum (PDB 4a05) [94], native laccase neus is known to be the strongest attacker among them, B from Trametes sp. (PDB 3kw7) [95], and lignin peroxidase followed by the genus of Polyporus [79]. Fortunately, al- from Trametes cervina (PDB 3q3u) [96]. (e full method- though being attacked by fungi, the chemical composition ology of this in silico prediction is provided in Supple- especially the essential oils can block it. Sri et al. confirmed mentary Materials. Table 2 presents the docking result of 10 that the cellulose content of cajuput wood was still relatively chemicals identified in cajuput against three enzymes high compared to other wood samples such as pine (Pinus merkusii), rubber (Hevea brasiliensis), and sengon (Para- expressed by fungi causing the wood decomposition process. (e 10 chemicals have a diverse structure bearing cyclic serianthes falcataria) after inoculated by the fungus as the decomposer [80]. monoterpene, sesquiterpene alcohol, allylbenzene alcohol, bicyclic sesquiterpene alcohol, acyclic monoterpene alcohol, (e wood decomposition is accelerated by the enzymatic process which is expressed by microorganism cells [81]. (is and acyclic monoterpene which could diverse the binding energy as well as its binding conformation. Figure 5 illus- enzymatic process includes hydrolysis as well as oxidation to trates the docking conformation of those 10 chemicals into degrade the cellulose [82] and to depolymerize the lignin the enzyme’s pocket site. [83]. (is degradation and depolymerization reduce the According to the binding energy, all chemicals occupied particle size of cellulose and lignin while dissolving them into water. As in common enzyme, the catalytic process is the pocket site of the three enzymes; however, they would rather interact with cellobiohydrolase than the laccase and limited by the substrate suitability, humidity, and temper- ature. On the one hand, a cellulose enzyme actively de- peroxidase due to the lower binding energy of cellobiohy- drolase compared to laccase and peroxidase. (is suggests composes cellulose into its soluble form yielding cellodextrin (6C), cellobiose (4C), and glucose (2C) [84]. On the other that the hydrolysis reaction could be the main mechanism of chemicals inhibition to the enzyme, which further led to hand, the activity of laccase and peroxidase degrade the blocking the wood decomposition process. All chemicals lignin into a red color product containing quinone as an also performed oxidation inhibition toward both oxidase oxidized product of guaiacol [85]. (e cellulose enzyme is 8 International Journal of Forestry Research Table 2: Binding energy of the interaction between chemicals in cajuput leaf oil and the enzymes (laccase, peroxidase, and cellobiohydrolase). Binding energy (kcal/mol) Chemicals Laccase Peroxidase Cellobiohydrolase 1, 8-Cineole −5.6 −5.6 −6.4 α-Eudesmol −6.3 −6.4 −7.8 β-Eudesmol −6.5 −6.4 −7.8 Eugenol −5.4 −6.2 −6.4 Guaiol −6.9 −7.8 −8.5 Isoeugenol −5.8 −6.5 −6.7 Linalool −5.5 −5.6 −6 Lupene −4.4 −9 −6.1 trans-β-Ocimene −5.1 −5.8 −6 Viridiflorol −6 −7 −8 (a) (b) (c) Figure 5: (e overlaid positions of 10 chemicals into the pocket site of (a) cellobiohydrolase, (b) laccase, and (c) peroxidase. (e proteins are presented as the surface form, and the ligands are presented as sticks from inside the proteins; yellow color represents carbon, red color represents oxygen, and white color represents hydrogen. enzymes. Lupene, on the one hand, exhibited the lowest contributed by hydrophobic interaction with Leu233, binding energy toward peroxidase among others. However, Leu239, Val160, Leu172, Leu171, Val183, and Phe46. on the other hand, lupene demonstrated the highest binding energy toward laccase associating with its lowest interaction 5. Discussion with the corresponding enzyme. Guaiol, which also is mostly deposited in conifers, showed the strongest affinity to either Cajuput has been broadly used in healthcare management laccase or cellobiohydrolase. (e 1, 8-cineole as the major including pharmaceutical inhalation dosage form, topical component in cajuput leaves also showed negative values in liquid for body warming, and aromatherapy, mainly due to the binding energy which is comparable to that of guaiol. its bioactivity and aromatic flavors. (e main part of cajuput (is finding suggests that lupene, 1, 8 cineole, and guaiol is the leaves that produce essential oil containing various play an important role in inhibiting the wood decomposing chemical substances such as 1, 8-cineole (eucalyptol), eu- process. genol, isoeugenol, guaiol, linalool, and viridiflorol. (e (e binding mode of guaiol into the pocket site of bioactivity of the chemicals varies due to their unique cellobiohydrolase is represented by hydrogen bond inter- molecular structure such as chiral carbon, rigidity-flexibility, actions between oxygen (OH)-Tyr170 and hydrogen (OH)- and stereoselectivity. (e bioactivity of plants against mi- Asp176 (Figure 6(a)). However, the stable conformation on croorganisms could be beneficial for many purposes, such as how guaiol performed the hydrogen bonds was supported by the development of medicine, product recycling process, and hydrophobic interaction between the sesquiterpene ring other waste management-based industry. with Trp367. (e interaction of guaiol with laccase Cajuput leaves produce solid waste which is not effi- (Figure 6(b)) was also elucidated showing H-bond inter- ciently reutilized unless for an organic fuel. Cajuput leaves action with Ile63. Nevertheless, the hydrophobic interaction appear not to be as biodegradable as other leaves. (is may was also performed through its sesquiterpene ring with due to the residue of the essential oils or other chemicals Ile46, Phe93, Val48, and Phe97. In the interaction between which has antimicrobial activities against bacteria, fungi, lupene and peroxidase (Figure 6(c)), there was no H-bond and termites. (e antimicrobial activities are potential for interaction observed. However, the lowest binding energy is the waste product to be used as a wood-preserving agent. International Journal of Forestry Research 9 LEU68 PHE46 ALA27 ARG43 ASP401 HIS47 GLN70 LEU171 TRP367 LEU172 ASP77 VAL168 HIS175 PHE97 MET158 ALA305 HIS64 ALA76 TYR170 ILE63 LEU239 ILE154 ASP176 LEV233 ILE46 ASP222 ASP146 VAL183 PHE93 VAL48 (a) (b) (c) Figure 6: (e binding conformation of (a) guaiol-cellobiohydrolase, (b) guaiol-laccase, and (c) lupene-peroxidase. (e proteins are presented as the line form, and the ligands are presented as thick stick forms; yellow color represents carbon, red color represents oxygen, and white color represents hydrogen. Many experiments investigating the activity of cajuput essential oils which have antimicrobial and insecticidal ac- essential oil as an antimicrobial agent have been performed. tivities. Further processing of the cajuput leaf solid waste Moreover, the detailed molecular mechanism on how the may increase the economic value of it. Guaiol, lupene, and plant fights against decomposition was well studied via in 1,8-cineole were predicted to be the chemicals having a silico and in vitro experiments. Some major chemicals in responsibility to those biological properties as predicted by cajuput essential oil were simulated using a computational an in silico study. In a future study, in vitro experiments molecular docking study, and as expected, several chemicals should be conducted to examine the corresponding enzyme were performing strong affinities with the enzyme of the activity in decomposing fungus against cajuput. microorganism such as fungi. (is molecular interaction can simply explain how the functional groups of the chemicals Data Availability interact with the important amino acid that surrounded the No data were used to support this study. pocket site of protein of interest [97]. Such interactions include hydrogen bond, hydrophobic bond, and even the strongest interaction, i.e., electrostatic interaction may exist. Conflicts of Interest Every single interaction contributes to the free energy of (e authors declare that there are no conflicts of interest binding. (e lower the free energy of binding (larger neg- regarding the publication of this paper. ative value), the stronger affinity between chemicals and the protein would be. Furthermore, the stronger affinity of chemicals toward protein leads to a higher chance of cajuput Acknowledgments to be the protein’s inhibitor associates with its anti-bio- (e authors thank Sendang Mole, the factory of cajuput decomposition effect. essential oil in Playen, Gunung Kidul, Yogyakarta, for do- (e in silico study could also be applied in other plants nating the cajuput leaves solid waste. (is project was fi- having similar properties. Guaiol in conifers has antimi- nancially supported by Sanata Dharma University Internal crobial [98] and insecticidal properties [99] due to the al- Research Grant 2020 with a special theme (006/LPPM USD/ coholic properties in the structure. (e strong interaction I/2020). between OH of guaiol and Tyr170 as well as Asp176 of cellobiohydrolase has been well studied using in silico docking as confirmed in the in silico prediction section. Supplementary Materials Other rational on how the 10 ligands are in silico predicted S1: the procedure of molecular docking using AutoDock to inhibit the activity of cellobiohydrolase are incorporated Vina Program. (Supplementary Materials) with in vitro results, that on the one hand, 1,8-cineole, α-eudesmol, β-eudesmol, eugenol, and isoeugenol actively inhibit the mycotoxigenic fungus [100, 101]. On the other References hand, linalool has been reported to have antifungal activity [1] G. K. Efruan, M. Martosupono, and F. S. Rondonuwu, against Candida albicans [102]. “Bioaktifitas senyawa 1,8 sineol pada minyak atsiri,” 2016. [2] J. J. Malakauseya, S. Sudjito, and M. N. Sasongko, “Pengaruh 6. 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A Review on the Potency of Melaleuca leucadendron Leaves Solid Waste in Wood Preservation and Its In Silico Prediction upon Biological Activities

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Copyright © 2020 Christine Patramurti et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi International Journal of Forestry Research Volume 2020, Article ID 8885259, 13 pages https://doi.org/10.1155/2020/8885259 Review Article A Review on the Potency of Melaleuca leucadendron Leaves Solid Waste in Wood Preservation and Its In Silico Prediction upon Biological Activities 1 2 1 Christine Patramurti , Radjali Amin , Christofori M. R. R. Nastiti , and Maywan Hariono Faculty of Pharmacy, Sanata Dharma University, Sleman, Daerah Istimewa, Yogyakarta 55282, Indonesia Post-Graduate School, Yogyakarta Institute of Technology, Bantul, Daerah Istimewa, Yogyakarta 55198, Indonesia Correspondence should be addressed to Maywan Hariono; mhariono@usd.ac.id Received 29 September 2020; Revised 29 October 2020; Accepted 3 November 2020; Published 17 November 2020 Academic Editor: Ahmad A. Omar Copyright © 2020 Christine Patramurti et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (e essential oils from cajuput leaves (Melaleuca leucadendron) have been well-known and applied, especially in healthcare management. However, the utilization of the leaves solid waste has not been explored and reported in detail. In this review, we elaborate on the cajuput leaves starting from the plant description and leaf morphology, chemical composition, biological activities, wood decomposing organism, and an in silico prediction upon its molecular mechanism. Based on the in silico prediction, compounds such as guaiol, lupene, and 1, 8-cineole have the potential to be antifungal and insecticide that associates with the cajuput potency as a wood preservative agent. in West Java, the waste production was up to 8.3 million tons 1. Introduction per year [3]. It is only about 14% of waste was estimated to be (e leaves and small branches distillation process of cajuput directly utilized by the cajuput distillation factory [4]. (Melaleuca leucadendron (L.) L.) produces essential oils with (e research reported that solid cajuput waste can be eucalyptol (cineole) as the main chemical substance used as activated charcoal [5]. (e waste can be further (50–65%) [1]. Eucalyptol (1, 3, 3-trimethyl-2-oxabicyclo processed as the biopellet and briquette charcoals [6]. (e [2.2.2]octane) is classified as the oxygenized monoterpene calorie value of cajuput briquette charcoal is much higher hydrocarbon group. (is compound plays an important role than the common briquette charcoals [2] that can reach up in its antibacterial activity against Gram-positive and Gram- to 1.5 times magnitude [7, 8]. (is solid waste also contains negative bacteria. (e biological activities were also reported volatile gases with a quantity of up to 47–68% [5, 7]. (is waste was also utilized as fuel such as in a steam boiler [9] against fungus and insects which could be due to that one of the major eucalyptol compounds borne a chemical structure and as a food substitute for cow cattle on the farm [10]. A as 1, 8-cineole (Figure 1) [1]. study by Rahmawati et al. reported that cajuput waste can be Besides the essential oils, the distillation process of processed as an organic soil fertilizer [4]; however, the cajuput produces solid residue (waste), i.e., the cajuput process of decomposition was slow triggering several studies leaves mixed with small and big branches. (e leaves solid to investigate the environmental factors accelerating this waste still contains the essential oil which composes waste decomposition process [11]. Interestingly, no study chemicals similar to its fresh leaves when they were distilled. has been carried out to investigate the chemical substances In Maluku (Indonesia), the waste was produced in ap- in cajuput solid waste which might slow down the de- proximately 51 million tons per year up to 2013 [2], whereas composition process. 2 International Journal of Forestry Research 3. Chemical Compositions H C CH Most of the chemical composition of cajuput was found H C from its leaves. (e (E, S)-nerolidol and related alcohols such as farnesol and geraniol were found from the leaves of Melaleuca leucadendron which was used in feeding deterrent of the gypsy moth larvae [24]. (e high content of two Figure 1: (e chemical structure of 1, 8-cineole. phenylpropanoid chemotypes was furthered isolated from the Melaleuca leaves, which were methyl eugenol (99%) and methyl isoeugenol (88%; both in Z and E configuration). On (e 1, 8-cineole which is one of the main components of the other hand, small amounts of trans-β-ocimene and eucalyptol [1] is predicted as the chemical which inhibits the linalool were also detected [25]. (e chemical structure of decomposition due to its activities as an antibacterial, an- eugenol, isoeugenol, trans-β-ocimene, and linalool is illus- tifungal, and insecticide agent. To date, no study identifies trated in Figures 3(a)–3(d), respectively. the concentration of 1, 8-cineole in the cajuput leaves solid By distillation, the fresh leaves of cajuput were producing waste and the probability of other compounds supporting essential oils containing a-pinene, β-pinene, β-myrcene, the role in the decomposition inhibition. It is estimated that limonene, c-terpinene, 1, 8-cineole, p-cymene, terpinolene, if these chemicals can be well isolated, they may be further benzaldehyde, linalool, trans-pinene hydrate, terpin-4-ol, utilized in the wooden furniture preservation, thereby in- c-terpineol, α-terpineol, 1-tetradecene, ledol, valencene, creasing the economic values of the solid cajuput waste. (is eugenol, α-eudesmol, and β-eudesmol as the main con- review article focuses on the progress studying the chemical stituents (64%) [15]. (e similar distillation process was constituent identification and the biological activities of carried out to hydrodistill essential oil from cajuput leaves cajuput leaves. Subsequently, the in silico prediction on how observing the other major constituents such as β-eudesmol the chemicals in cajuput leaves solid waste interact with the (15.8%), α-eudesmol (11.3%), viridiflorol (8.8%), and guaiol protein expressed by wood decomposing microorganisms is (9.0%) (Figures 3(e)–3(h), respectively) [26]. also reviewed. A study by Yoshida et al. on the chemical identification of cajuput dried fruits indicated a new hydrolyzable tannin and other polyphenols as the secondary metabolite being 2. Plants Description and Leaf Morphology deposited. (ey were 1, 2-di-O-galloyl-3-O-digalloyl-4, 6-O- (S)-hexahydroxydiphenoyl-3-Iβ-glucose (Figure 4(a)) and (e genus of Melaleuca (Myrtaceae family) covers at least 230 species in the world, mostly found in Tasmania (Aus- nine known hydrolyzable tannins. Commonly known stil- bene glycoside and triterpene were also identified [27]. tralia), Indonesia, Papua New Guinea, Tropical America, A comprehensive study was successfully performed to and South Asia [12, 13]. (e main genera utilized for the production of commercial essential oils and aromatherapy identify further triterpene from the leaves and heartwood of cajuput. A novel lupene-type nortriterpene (28-norlup-20(29)- are Melaleuca alternifolia (Maiden and Betche) Cheel (tea tree oil), Melaleuca cajuputi Powell (cajuput oil), and ene-3β, 17β-diol) as well as 13 other known compounds were characterized. (e other 13 compounds were (2E, 6E)-farnesol, Melaleuca quinquenervia (Cav.) S. T. Blake (niaouli oil). Other well-known genera are Melaleuca leucadendron, phytol, squalene, alloaromadendrene, ledene, palustrol, vir- idiflorol, ledol, betulinaldehyde, betulinic acid, 3β-acetyl-lup- Melaleuca viridiflora, Melaleuca acacioides, Melaleuca alsophila, Melaleuca bracteata, and Melaleuca argentea 20(29)-en-28-oic acid, 3-oxolup-20(29)-en-28-oic acid, and platanic acid [28]. Further novel triterpenes were characterized, [14, 15]. (e trees of Melaleuca leucadendron are approxi- mately 40m high, which is grown in northern Australia, the i.e., 3β-cis-coumaroyloxy-2α-hydroxyursa-12, 20(30)-dien-28- oicacid, and cis- and trans-3β-caffeoyloxy-2α-hydroxyurs-12- south coast of New-Guinea, and the east coasts of Indonesia en-28-oic acids from the leaves as well [29]. Research also [12]. (e morphology of Melaleuca leucadendron leaves is a blade narrowly ovate, very narrowly ovate, rarely narrowly successfully identified three new triterpenes from the heart- wood of cajuput [30]. (ey are 23-trans-p-coumaroyloxy-2α, elliptic, or very narrowly elliptic (often falcate to subfalcate). (e leaves are 3.5–16 times longer compared to the width; 3β-dihydroxyolean-12-en-28-oic acid, 3β-trans-caffeoyloxy- 2α,23-dihydroxyolean-12-en-28-oic acid, and its isomer 3p- petals are with elliptic oil glands (occasionally long elliptic glands form an apparently linear gland) [16]. (e tree of cis-caffeoyloxy-2α, 23-dihydroxyolean-12-en-28-oic acid [31]. (e general structure of lupene is shown in Figure 4(b). cajuput and its leaves are presented in Figure 2. A number of protocols have been applied to standardize the components Having isolated from the heartwood, four new tri- terpenes were characterized including eupha-7, 24-diene-3α, of the leaves and the extract including phytochemical screening, thin layer chromatography profile, organoleptic 22α-diol, 20-taraxastene-3R, 28-diol, 3R-hydroxy-13(18)- oleanene-27, 28-dioic acid, and 3R, 27-dihydroxy-28, 20α- evaluation, histological and microscopic techniques of taraxastanolide. Besides, Lee also identified four novel leaves, powder microscopic, physicochemical parameters, quantitative microscopy, and evaluation of volatile oil β-triketone flavanones from the leaves. (e compounds were then named as leucadenone A to leucadenone D [32]. [17–23]. International Journal of Forestry Research 3 (a) (b) Figure 2: (e habitus of (a) tree of cajuput and (b) its leaves. (e photos were taken in Sendang Mole, Playen, Gunung Kidul, Daerah Istimewa Yogyakarta. CH CH CH CH 2 3 2 3 OH CH HO HO CH H C H C 3 3 H C CH 3 3 H C CH 3 3 (a) (b) (c) (d) OH OH H C H H C 3 CH H C CH 3 HO 3 3 C CH H C 3 3 H C CH H C 3 H C H C 3 CH H C H C 2 3 H C H C OH CH (e) (f) (g) (h) Figure 3: (e chemical structure of (a) eugenol, (b) isoeugenol, (c) trans-β-ocimene, (d) linalool (e) β-eudesmol, (f) α-eudesmol, (g) viridiflorol, and (h) guaiol which are benefit for the antibacterial effect and are the components of hydrodistilled essential oil from cajuput leaves. 4 International Journal of Forestry Research HO HO CH OH O H C HO HO HO OH HO H C CH 3 3 CH HO H C 3 CH O O H C HO 3 CH CH OH HO (a) (b) Figure 4: (e chemical structure of (a) 1, 2-di-O-galloyl-3-O-digalloyl-4, 6-O-(S)-hexahydroxydiphenoyl-3-Iβ-glucose, the chemical composition of cajuput fruits, and (b) the general structure of lupene which are the chemical composition of the leaves. Table 1: Identification and quantification of the compounds in cajuput (Melaleuca leucadendron) (reported in 2011–2020). No. Compounds Part % or mg References 1 α-Pinene Leaves 0.22–0.68 [33] 2 α-(ujene Leaves 1.29–4.16 [33] 3 β-Pinene Leaves 0.79–2.90 [33] 4 β-Myrcene Leaves 0.31–0.95 [33] 5 Carene Leaves 0.29–1.18 [33] 6 D (+)-limonene Leaves 4.45–8.85 [33] 7 c-Terpinene Leaves 1.82–6.72 [33] 8 Terpinolene Leaves 0.67–3.62 [33] 9 1,8-Cineole Leaves 44–60 [33] 10 Linalool Leaves 0.00–0.42 [33] 11 Terpinene-4-ol Leaves 0.63–0.97 [33] 12 Ocimenol Leaves 0.09–0.20 [33] 13 α-Terpineol Leaves 5.93–12.45 [33] 14 c-Terpineol Leaves 0.36–2.06 [33] 15 Cedrene Leaves 0.00–0.61 [33] 16 β-Caryophyllene Leaves 3.78–7.64 [33] 17 Humulene Leaves 0.53–0.88 [33] 18 β-Eudesmene Leaves 0.98–3.51 [33] 19 Patchoulene Leaves 0.82–4.37 [33] 20 Germacrene D Leaves 0.17–0.60 [33] 21 Aromadendren Leaves 0.00–0.27 [33] 22 Globulol Leaves 2.70–3.60 [33] 23 Viridiflorol Leaves 0.00–0.36 [33] 24 Eugenol Leaves 2.68–4.85 [33] 25 2-Pentanone Leaves 5.0mg [33] 26 Melachromone Leaves 2.4mg [34] 27 Parietin Leaves 33.2mg [34] 28 5-Hydroxy-7-methoxy-2, 6, 8-trimethylchromone Leaves 11.7mg [34] 29 Eugenitin Leaves 10.2mg [34] 30 2, 5-Dihydroxy-7-methoxy-2, 6-dimethylchromanone Leaves [34] 31 2, 5-Dihydroxy-7-methoxy-2, 8-dimethylchromanone Leaves 2.4mg [34] 32 Noreugenin Leaves 8.3mg [34] 33 5, 7-Dihydroxy-2, 6, 8-trimethylchromone Leaves 4.8mg [34] 34 Methyl 2-acetyl-3, 5-dihydroxyphenylacetate Leaves 14.4mg [34] 35 Quercitrin Leaves 3.0mg [34] 36 β-Sitosterol Leaves 8.0mg [34] 37 5-Hydroxy-7, 40-dimethoxy-6, 8-dimethylflavone Leaves 12mg [34] 38 3, 3′, 4-Tri-O-methylellagic acid Leaves 0.04 [34] 39 Camphene Leaves 0.14 [35] International Journal of Forestry Research 5 Table 1: Continued. No. Compounds Part % or mg References 40 L-limonene Leaves 0.04 [35] 41 Rose oxide Leaves 0.13 [35] 42 Isopulegol Leaves 0.24 [35] 43 Neral Leaves 0.13 [35] 44 Geraniol Leaves 0.31 [35] 45 Geranial Leaves 0.14 [35] 46 A-terpenyl acetate Leaves 0.23 [35] 47 Δ-Elemene Leaves 0.37 [35] 48 α-Ylangene Leaves 0.36 [35] 49 α-Cubebene Leaves 1.01 [35] 50 β-Elemene Leaves 0.16 [35] 51 α-Gurjunene Leaves 0.55 [35] 52 Linalyl acetate Twigs 0.11 [36, 37] 53 Bornyl acetate Leaves 0.60 [36, 37] 54 β-Bourbonene Flowers 2.67 [36, 37] 54 (E)-β-Farnesene Flowers 0.10 [36, 37] 55 (Z)-Nerolidol Twigs 90.85 [36, 37] 56 (E)-Nerolidol Leaves 0.20 [36, 37] 57 Epi-α-cadinol Leaves 0.79 [36, 37] 58 β-Bisabolol Flowers 0.25 [36, 37] 59 (Z)-Nerolidyl acetate Twigs 0.25 [36, 37] 60 Palustrol Leaves 1.86 [36, 37] 61 Ledol Leaves 0.87 [36, 37] 62 Bulnesol Leaves 0.21 [36, 37] 63 Alloaromadendrene Leaves NR [36, 37] 64 Melaleucadines A Branches and leaves NR [38] 65 Melaleucadines B Branches and leaves 0.8 [38] 66 3-Allyl-2-methoxyphenol Leaves 0.8 [39] 67 (E)-Methyl cinnamate Leaves 95.4 [39] 68 Eugenol methyl ether Leaves NR [39] 69 (E)-3, 7-Dimethylocta-2, 6-dienal Leaves NR [40] 70 1, 1, 4, 7-Tetramethyl-1a, 2, 3, 4, 4a, 5, 6, 7b-octahydro- Leaves NR [40] 71 1H-cyclopropa[e]azulene Fruits NR [41] 72 (+)-Leumelaleucol A Fruits NR [41] 73 (−)-Leumelaleucol A Fruits NR [41] 74 Leumelaleucol B Fruits NR [41] 75 Leumelaleucol C Fruits NR [41] 76 Leumelaleucol D Fruits NR [41] 77 Leumelaleucol E Fruits NR [41] 78 Leumelaleucol F Fruits NR [41] 79 Leumelaleucol G Fruits NR [41] 80 Leumelaleucol H Fruits NR [41] 81 Leumelaleucol I Fruits NR [41] 82 Leumelaleucol J Fruits NR [41] NR, not reported. (e investigation of the chemical component in the 4.1. Antibacterial. Cajuput oil, which was hydrodistilled from the leaves, was tested against the methicillin-resistant cajuput has been highly developed in a decade. Novel and known compounds were reported enriching the database of Staphylococcus aureus (MRSA) colony [42]. (e minimum compounds from cajuput (Table 1), which were potential to bactericidal concentration (MBC) and the minimum inhi- be developed as medicine, cosmetics, aromatherapy, and bition concentration (MIC) were found to be 0.2% and 0.4%, fiber technology. respectively. (is suggested that the leaves oil was able to inhibit the resistant bacteria growth in very low concen- trations. (is finding could be the potential to overcome 4. Biological Activities bacterial resistance which has currently become an urgent public health issue. Furthermore, the antibacterial test (e preservative effect of cajuput leaves was introduced due to its chemical composition to eradicate microorganisms. Bio- against MRSA was also carried out on the ethanol extract of cajuput leaves. Maceration was used to extract the bacte- logical activities of cajuput against some microbes including ricidal constituents from the leaves, and the extract was bacteria, fungi, virus, and insects are summarized below. 6 International Journal of Forestry Research tested onto the bacteria using a good well diffusion method. subject of the study for sure. A study by Farag et al. on HSV- (e results demonstrated that ethanol extract was able to 1 was also conducted to evaluate the antiviral activity of the fresh leaves oil of cajuput. (is supported the previous inhibit the growth of bacteria. (e concentrations of 50%, 60%, 70%, 80%, 90%, and 100% showed an inhibition zone of finding that cajuput was able to inhibit HSV-1 which in- 17.2mm, 18.1mm, 19.1mm, 19.4mm, 19.7mm, and fected African green monkey kidney cells (Vero cell) with 20.1mm, respectively [43]. (e ethanol extract of cajuput oil 92% of inhibition [15]. was also previously inhibiting Escherichia coli bacterial growth with an MIC of 64 µg/mL [44]. 4.4. Repellent Activity. Cajuput leaf oil demonstrated re- Cajuput essential oil from leaves demonstrated appre- pellent activities against Aedes (43.2%), Anopheles (100%), ciable activity against Enterobacter aerogenes with inhibition and Culex mosquitoes (100%) during eight hours of mos- zone 13.7–16.2mm [39]. Enterobacter aerogenes is the quito exposure [56]. When the oil was tested into the larvae Gram-negative bacteria of the Enterobacteriaceae family of Aedes, it showed the larvicidal activity up to 3.3% at a causing bacterial infection in the wound and the respiratory concentration of 50ppm [57]. A similar study was con- as well as the urinary tract [45]. ducted by Noosidum et al. confirming the repellent activity of the oil against female Aedes aegypti mosquitoes. A high 4.2. Antifungal. (e antifungal activity of the cajuput leaf escape rate of the mosquitoes was observed for up to 24 essential oils had been determined against Fusarium hours [58]. oxysporum, 7anatephorus cucumeris, and Rhizopus ory- Further insect repellent activities of cajuput leaf oils against the vector of dengue and filariasis were reported zae [46]. (e results showed that the oils were active against F. oxysporum with IC 0.01–0.11 mg/mL and [59, 60]. (e oil was showing 97.5% repellency when it was exposed to Lasioderma serricorne, which was a serious pest against 7anatephorus cucumeris with IC 0.52–4.20 mg/ mL, but less active against R. oryzae as it only showed of tobacco leaves cigarettes, cocoa beans, cereals, oilseeds, IC of 1.35–7.61 mg/mL. Fusarium oxysporum is a soil- pulses, spices, and dried fruits [61]. Another study of the borne pathogen bacteria that cause vascular wilts in repellency effect of cajuput leaf oils against Sitotroga cere- several plants [47]. 7anatephorus cucumeris which is alella was also reported. (e oil repelled up to 61% after the classified as basidiomycetes also causes plant diseases to photo natural period of Sitotroga cerealella, a Lepidoptera numerous agricultural and horticultural plants worldwide insect which causes an unpleasant smell of grains [62]. [48]. Rhizopus oryzae is a parasitic fungus that penetrates Cajuput leaf oils were also reported to have repellent ac- in the citrus fruit tissue through microwounds and tivities against Plutella xylostella, the most important pest in cabbage [63]. bruises [49]. Along with the above studies, the antifungal assay of cajuput leaf oils was also determined against Fomitopsis 4.5. Wood Decomposing Organisms. Organic material de- palustris, Tinea versicolor, and Chaetomium globosum. composition is carried out by microbes or mesofauna. (is According to Rini et al., the cajuput leaf oils demonstrated process breaks down the materials into basic elements such antifungal activities with IC 0.12–3.16mg/mL, as N, P, K, Mg, and Ca, which are important for soil nu- 0.01–0.06mg/mL, and 0, 06–0.15mg/mL for Fomitopsis trients [64]. (e microbes or mesofauna are often utilized as palustris, Tinea versicolor, and Chaetomium globosum, re- wood decomposers especially for the lignin and cellulose spectively [50]. F. palustris enzymatically breaks down the matters [65]. (ese decomposers are divided into primary cellulose of wood and leads to the plant disease namely and secondary decomposers. brown rot [51], whereas Chaetomium globosum is an en- (e primary decomposer is a mesofauna such as Col- dophytic fungus assisting the cellulose decomposition of lembola and Acarina which converts large particles into plant cells [52]. T. versicolor which is known as a turkey tail micronized sizes [66]. A wood decomposition process is also mushroom exhibits anticancer activities due to the poly- generally related to macrowood decomposers, which could saccharide constituents [53]. Candidiasis is a fungal infec- be insects and termites [67]. When the trees are logged tion which commonly occurs in female, particularly in the down, the decomposers start to attack the wood, especially to female reproductive organ. (e cajuput leaf oils potentially that sapwood which is rich in cellulose and carbohydrate. eradicated the Candida albicans with MIC 62.5 µg/mL which (e moist environment further supports the existence of the is comparable to ketoconazole, the well-known synthetic wood decomposers in the trees [68]. Hollowish trees in- drug used to treat candidiasis [54]. cluding rubber (Hevea brasiliensis), palm oil (Elaeis sp.), walnuts (Canarium vulgare), and fire tree (Delonix regia) are 4.3. Antivirus. (e potential antiviral activity of cajuput commonly attacked by ground/subterranean termites (ge- aqueous and methanol extracts were investigated against nus of Coptotermes) [69]. herpes simplex virus-1 (HSV-1) [55]. (e aqueous extract (e wood decomposition process quickly occurs once demonstrated a 55.6% plaque reduction activity. Interest- the trees died or fallen down. (is is because neither defense nor a tree recovery is leading to the direct contact between ingly, at the same concentration (100 µg/mL), the methanol extract exhibited a 100% plaque reduction defining the the dead trees with the ground rich of decomposers. (is attack is also performed by the genus of Coptotermes due to antiviral effect of such a plant against HSV-1. (is poten- tially reduced the mouse skin lesions and the mortality of the the chemical substance such as eugenol which attracts the International Journal of Forestry Research 7 expressed by Chaetomium sp. [86], whereas the laccase and termites to come over the trees [70]. Moreover, a derivative of eugenol, i.e., methyl eugenol (C H O ) has a function to peroxidase enzyme are produced by the genus of Trametes 12 24 8 [87]. stimulate the olfactory sensory organ in termites [71]. In conjunction with this, the termites have been successfully identified as a living wood attacker to cajuput which is the 4.6. In silico Prediction of the Antidecomposing Effect of genus of Odontotermes [72]. Focusing on the cajuput tree, the Macrotermes gilvus termites attack is unavoidable even Cajuput. In silico method can be potentially used to study the activity of chemical substances in cajuput oil regarding though the trees are still growing [73], especially to those of roots as well as the branches [74]. the inhibition effect to the decomposing microbial enzymes. Interaction between the 3D structure of the enzyme and the Muslich and Rulliaty examined the durability of the molecule structure of the chemical of interest can be well processed wood of cajuput from three types of decomposer’s investigated by using computational methods [88, 89]. One attack, i.e., dried ground termites (Cryptotermes cyn- of the methods is molecular docking, carried out by pre- ocephalus Light), common ground termites (Coptotermes dicting the free energy of binding as well as its conformation curvignathus Holmgren), and marine wood termites con- between micromolecule (chemical) and macromolecule clude that cajuput is resistant toward the attack of Copto- termes curvignathus but is vulnerable toward other (enzyme) [90]. Once the chemical of the oil interacts with an enzyme (by giving a negative value in the binding energy decomposers [75]. (is protective effect might be due to the chemical constituent such as cineole, melaleucin, and ter- along with its stable conformation), this conformation blocked the enzyme catalytic function in the decomposition pineol [76]. (e secondary decomposers are mostly in the form of process. (e 3D structure of the enzyme is collected from a fungi, including Trichoderma reesei, Trichoderma harzia- protein data bank (http://www.rcsb.org), which is a form of num, Trichoderma koningii, Phanerochaete chrysosporium, cryopurified enzyme crystal [91, 92]. (e crystal is then Cellulomonas, Pseudomonas, 7ermospora, Aspergillus photographed in a three-dimensional form using an X-ray Niger, Aspergillus terreus, Penicillium, and Streptomyces [77]. crystallography method. (e docking software will be fur- According to Eriksson et al., fungus is the most active de- ther used to predict the activity of such enzyme including composer which immediately converts organic materials into simpler organic elements [78]. Suprapti and Djarwanto their inhibition by using this 3D crystal. (is technique is very popular in the drug discovery process through enzyme successfully identified some fungi attacked to cajuput in- cluding Pycnoporus sanguineus, Polyporus, Trametes, inhibition that blocks pathogenic diseases [93]. In this section, we predicted the capability of some major Schizophyllum commune, Chaetomium globosum, Mar- asmius, and Dacryopinax spathularia. Pycnoporus sangui- chemicals in cajuput to interact with cellobiohydrolase from Chaetomium thermophilum (PDB 4a05) [94], native laccase neus is known to be the strongest attacker among them, B from Trametes sp. (PDB 3kw7) [95], and lignin peroxidase followed by the genus of Polyporus [79]. Fortunately, al- from Trametes cervina (PDB 3q3u) [96]. (e full method- though being attacked by fungi, the chemical composition ology of this in silico prediction is provided in Supple- especially the essential oils can block it. Sri et al. confirmed mentary Materials. Table 2 presents the docking result of 10 that the cellulose content of cajuput wood was still relatively chemicals identified in cajuput against three enzymes high compared to other wood samples such as pine (Pinus merkusii), rubber (Hevea brasiliensis), and sengon (Para- expressed by fungi causing the wood decomposition process. (e 10 chemicals have a diverse structure bearing cyclic serianthes falcataria) after inoculated by the fungus as the decomposer [80]. monoterpene, sesquiterpene alcohol, allylbenzene alcohol, bicyclic sesquiterpene alcohol, acyclic monoterpene alcohol, (e wood decomposition is accelerated by the enzymatic process which is expressed by microorganism cells [81]. (is and acyclic monoterpene which could diverse the binding energy as well as its binding conformation. Figure 5 illus- enzymatic process includes hydrolysis as well as oxidation to trates the docking conformation of those 10 chemicals into degrade the cellulose [82] and to depolymerize the lignin the enzyme’s pocket site. [83]. (is degradation and depolymerization reduce the According to the binding energy, all chemicals occupied particle size of cellulose and lignin while dissolving them into water. As in common enzyme, the catalytic process is the pocket site of the three enzymes; however, they would rather interact with cellobiohydrolase than the laccase and limited by the substrate suitability, humidity, and temper- ature. On the one hand, a cellulose enzyme actively de- peroxidase due to the lower binding energy of cellobiohy- drolase compared to laccase and peroxidase. (is suggests composes cellulose into its soluble form yielding cellodextrin (6C), cellobiose (4C), and glucose (2C) [84]. On the other that the hydrolysis reaction could be the main mechanism of chemicals inhibition to the enzyme, which further led to hand, the activity of laccase and peroxidase degrade the blocking the wood decomposition process. All chemicals lignin into a red color product containing quinone as an also performed oxidation inhibition toward both oxidase oxidized product of guaiacol [85]. (e cellulose enzyme is 8 International Journal of Forestry Research Table 2: Binding energy of the interaction between chemicals in cajuput leaf oil and the enzymes (laccase, peroxidase, and cellobiohydrolase). Binding energy (kcal/mol) Chemicals Laccase Peroxidase Cellobiohydrolase 1, 8-Cineole −5.6 −5.6 −6.4 α-Eudesmol −6.3 −6.4 −7.8 β-Eudesmol −6.5 −6.4 −7.8 Eugenol −5.4 −6.2 −6.4 Guaiol −6.9 −7.8 −8.5 Isoeugenol −5.8 −6.5 −6.7 Linalool −5.5 −5.6 −6 Lupene −4.4 −9 −6.1 trans-β-Ocimene −5.1 −5.8 −6 Viridiflorol −6 −7 −8 (a) (b) (c) Figure 5: (e overlaid positions of 10 chemicals into the pocket site of (a) cellobiohydrolase, (b) laccase, and (c) peroxidase. (e proteins are presented as the surface form, and the ligands are presented as sticks from inside the proteins; yellow color represents carbon, red color represents oxygen, and white color represents hydrogen. enzymes. Lupene, on the one hand, exhibited the lowest contributed by hydrophobic interaction with Leu233, binding energy toward peroxidase among others. However, Leu239, Val160, Leu172, Leu171, Val183, and Phe46. on the other hand, lupene demonstrated the highest binding energy toward laccase associating with its lowest interaction 5. Discussion with the corresponding enzyme. Guaiol, which also is mostly deposited in conifers, showed the strongest affinity to either Cajuput has been broadly used in healthcare management laccase or cellobiohydrolase. (e 1, 8-cineole as the major including pharmaceutical inhalation dosage form, topical component in cajuput leaves also showed negative values in liquid for body warming, and aromatherapy, mainly due to the binding energy which is comparable to that of guaiol. its bioactivity and aromatic flavors. (e main part of cajuput (is finding suggests that lupene, 1, 8 cineole, and guaiol is the leaves that produce essential oil containing various play an important role in inhibiting the wood decomposing chemical substances such as 1, 8-cineole (eucalyptol), eu- process. genol, isoeugenol, guaiol, linalool, and viridiflorol. (e (e binding mode of guaiol into the pocket site of bioactivity of the chemicals varies due to their unique cellobiohydrolase is represented by hydrogen bond inter- molecular structure such as chiral carbon, rigidity-flexibility, actions between oxygen (OH)-Tyr170 and hydrogen (OH)- and stereoselectivity. (e bioactivity of plants against mi- Asp176 (Figure 6(a)). However, the stable conformation on croorganisms could be beneficial for many purposes, such as how guaiol performed the hydrogen bonds was supported by the development of medicine, product recycling process, and hydrophobic interaction between the sesquiterpene ring other waste management-based industry. with Trp367. (e interaction of guaiol with laccase Cajuput leaves produce solid waste which is not effi- (Figure 6(b)) was also elucidated showing H-bond inter- ciently reutilized unless for an organic fuel. Cajuput leaves action with Ile63. Nevertheless, the hydrophobic interaction appear not to be as biodegradable as other leaves. (is may was also performed through its sesquiterpene ring with due to the residue of the essential oils or other chemicals Ile46, Phe93, Val48, and Phe97. In the interaction between which has antimicrobial activities against bacteria, fungi, lupene and peroxidase (Figure 6(c)), there was no H-bond and termites. (e antimicrobial activities are potential for interaction observed. However, the lowest binding energy is the waste product to be used as a wood-preserving agent. International Journal of Forestry Research 9 LEU68 PHE46 ALA27 ARG43 ASP401 HIS47 GLN70 LEU171 TRP367 LEU172 ASP77 VAL168 HIS175 PHE97 MET158 ALA305 HIS64 ALA76 TYR170 ILE63 LEU239 ILE154 ASP176 LEV233 ILE46 ASP222 ASP146 VAL183 PHE93 VAL48 (a) (b) (c) Figure 6: (e binding conformation of (a) guaiol-cellobiohydrolase, (b) guaiol-laccase, and (c) lupene-peroxidase. (e proteins are presented as the line form, and the ligands are presented as thick stick forms; yellow color represents carbon, red color represents oxygen, and white color represents hydrogen. Many experiments investigating the activity of cajuput essential oils which have antimicrobial and insecticidal ac- essential oil as an antimicrobial agent have been performed. tivities. Further processing of the cajuput leaf solid waste Moreover, the detailed molecular mechanism on how the may increase the economic value of it. Guaiol, lupene, and plant fights against decomposition was well studied via in 1,8-cineole were predicted to be the chemicals having a silico and in vitro experiments. Some major chemicals in responsibility to those biological properties as predicted by cajuput essential oil were simulated using a computational an in silico study. In a future study, in vitro experiments molecular docking study, and as expected, several chemicals should be conducted to examine the corresponding enzyme were performing strong affinities with the enzyme of the activity in decomposing fungus against cajuput. microorganism such as fungi. (is molecular interaction can simply explain how the functional groups of the chemicals Data Availability interact with the important amino acid that surrounded the No data were used to support this study. pocket site of protein of interest [97]. Such interactions include hydrogen bond, hydrophobic bond, and even the strongest interaction, i.e., electrostatic interaction may exist. Conflicts of Interest Every single interaction contributes to the free energy of (e authors declare that there are no conflicts of interest binding. (e lower the free energy of binding (larger neg- regarding the publication of this paper. ative value), the stronger affinity between chemicals and the protein would be. Furthermore, the stronger affinity of chemicals toward protein leads to a higher chance of cajuput Acknowledgments to be the protein’s inhibitor associates with its anti-bio- (e authors thank Sendang Mole, the factory of cajuput decomposition effect. essential oil in Playen, Gunung Kidul, Yogyakarta, for do- (e in silico study could also be applied in other plants nating the cajuput leaves solid waste. (is project was fi- having similar properties. Guaiol in conifers has antimi- nancially supported by Sanata Dharma University Internal crobial [98] and insecticidal properties [99] due to the al- Research Grant 2020 with a special theme (006/LPPM USD/ coholic properties in the structure. (e strong interaction I/2020). between OH of guaiol and Tyr170 as well as Asp176 of cellobiohydrolase has been well studied using in silico docking as confirmed in the in silico prediction section. Supplementary Materials Other rational on how the 10 ligands are in silico predicted S1: the procedure of molecular docking using AutoDock to inhibit the activity of cellobiohydrolase are incorporated Vina Program. (Supplementary Materials) with in vitro results, that on the one hand, 1,8-cineole, α-eudesmol, β-eudesmol, eugenol, and isoeugenol actively inhibit the mycotoxigenic fungus [100, 101]. On the other References hand, linalool has been reported to have antifungal activity [1] G. K. Efruan, M. Martosupono, and F. S. Rondonuwu, against Candida albicans [102]. “Bioaktifitas senyawa 1,8 sineol pada minyak atsiri,” 2016. [2] J. J. Malakauseya, S. Sudjito, and M. N. Sasongko, “Pengaruh 6. 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Published: Nov 17, 2020

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