Phytochemicals, pharmacological and ethnomedicinal studies of Artocarpus: A scoping review

Siti Mariam A Lathiff, Norzafneza M Arriffin, Shajarahtunnur Jamil

Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, 81310 Johor Bahru, Johor, Malaysia

ABSTRACT

KEYWORDS: Artocarpus; Phytochemistry; Pharmacological activities; Ethnomedicine; Flavonoids

1. Introduction

Genus Artocarpus is one of the important groups of plants that belongs to the Moraceae family. A total of 55 Artocarpus species spread throughout East Asia, South Asia, Southeast Asia to the New Guinea and southern Pacific[1,2]. Up to 2020, a total of 32 Artocarpus species and another two varieties were discovered in Malaysia[2-4].Some Artocarpus species have edible fruits that led to cultivations for the products. The fruits can be eaten as soon as it is ripe. Most are eaten fresh after they are ripe, fried with batter, or served as desserts. The seed can also be eaten after boiling, baking, roasting,or frying[5]. Our investigation on Artocarpus species started since we did our own phytochemical and pharmacological research. Although several reviews on Artocarpus species had been published, the objectives and focus are very much different from this article[6,7].

In this article, we focus on reviewing the phytochemistry and pharmacological studies of Artocarpus species available in Malaysia.But before we dive into that, we need to know the distribution and availability of Artocarpus species in Malaysia. Then from this data,we gathered the reported ethnomedicinal usage from all around the world related to these Artocarpus species. The ethnomedicinal data are important to understand its relationship with the pharmacological activities tested[8]. All the data are tabulated in Table 1 for better understanding.

2. Methodology

Literature was searched using various engines such as The Web of Science, PubMed, Science Direct, Scopus, Research Gate, and Google Scholar. The search term ‘Artocarpus’, ‘Artocarpus Malaysia’,‘Artocarpus extracts’, ‘Artocarpus traditional medicine’ and ‘Artocarpus ethnomedicine’ were used without limitations. The references cited from the retrieved articles were scanned and cross-checked. Other than published articles, information on Artocarpus species were also obtained from books published by reliable sources. The distribution,morphology, and ethnobotanical information of Artocarpus species were obtained from books published under the Ministry of Agriculture, Malaysia, and Forest Research Institute of Malaysia.All published researches on phytochemistry and pharmacological activities of Malaysia’s Artocarpus species up to January 2021 were included in this review.

3. Morphology and distributions

Artocarpus trees are mostly evergreen with thick white latex.Their leaves are spirally arranged or alternate. While Artocarpus fruits have different sizes from small to large with fleshy seeds that are mostly large and embedded in the head of the fruit and surrounded by a waxy or pulpy succulent layer. The sapwood has various shades of light yellow which can be differentiated from the heartwood that has different shades of brown and sometimes traces of olive green. Artocarpus produces two types of hardwood,light and medium hardwood. Other than its edible fruits, Artocarpus is also well known for its valuable timber in Malaysia. The light hardwood timber is known as terap in Peninsular Malaysia and Sabah or pudau in Sarawak. The medium hardwood is known as keledang in Peninsular Malaysia, beruni in Sabah and selangking in Sarawak[2,3]. Kochummen identified 20 species of Artocarpus in Malaysia including two incompletely known species and reported in Tree Flora of Malaya[3]. Another book was published specifically for Sabah and Sarawak (East Malaysia) that confirmed the availability of 20 species with one incompletely known species[2]. These two reports conclude a total of 32 Artocarpus species and another two varieties in Malaysia. Distribution of identified Artocarpus in Malaysia is listed in Table 1.

4. Ethnomedicine

Ethnomedicine is the study of the cultural concept of health, disease and illness using nature[9]. There are several published articles on ethnomedicine practices using different parts of Artocarpus by certain tribes or specific locations in the world[10-16]. Table 1 highlights available Artocarpus species discovered in Malaysia including their ethnomedicine practices worldwide.

Table 1. Distribution and availability of Artocarpus species in Malaysia and their ethnomedicinal uses (continued).

Table 1. Distribution and availability of Artocarpus species in Malaysia and their ethnomedicinal uses (continued).

Table 1. Distribution and availability of Artocarpus species in Malaysia and their ethnomedicinal uses (continued).

Table 1. Distribution and availability of Artocarpus species in Malaysia and their ethnomedicinal uses.

5. Phytochemistry

A total of 61 compounds were isolated from Artocarpus species collected from different locations in Malaysia. These compounds fall under the flavonoids (chalcones, flavones, flavanones, flavanols,flavonols), xanthones, stilbenoid as well as terpenoids, and sterols.Flavonoids are present in all Artocarpus species and proved to be the chemotaxonomic marker of Artocarpus plants. The structures of compounds 1-61 are shown in Supplementary Figures 1-5.

5.1. Phenolics secondary metabolites

5.1.1. Chalcones

Two separate studies of Artocarpus lowii (A. lowii) from Terengganu reported the isolation of two new dihydrochalcones.These chalcones are named as 2′,4′-dihydroxy-4-methoxy-3′-prenyldihydrochalcone (1) and 2′,4′-dihydroxy-3,4-(2″,2″-dimethylchromeno)-3′-prenyldihydrochalcone (2)[17,18]. Another two chalcones were also isolated and known as isobavachalcone(3) and 4-hydroxyonchocarpin (4)[17-19]. Isobavachalcone (3) was also isolated from Artocarpus anisophyllus (A. anisophyllus) collected from Johor[20]. In 2016, two new prenylated chalcones were reported from A. lowii collected from Selangor. These chalcones are identified as 2-hydroxyparatocarpin (5) and 2′,3,4′,4-tetrahydroxy-3′-prenylchalcone (6)[21]. A study on the leaves of Artocarpus fulvicortex(A. fulvicortex) from Terengganu, Malaysia gave 2′-hydroxy-4,4′,6′-trimethoxychalcone (7)[22]. In 2013, two new dihydrochalcones named elastichalcone A (8) and elastichalcone B (9) were isolated from the leaves of Artocarpus elasticus (A. elasticus) collected from Selangor, Malaysia[23]. The structures of all chalcones are presented in Supplementary Figure 1.

5.1.2. Flavones

Artonin E (10), a known flavone with four hydroxyl groups,a prenyl, and a chromeno ring was isolated from the barks of Artocarpus scortechinii (A. scortechinii), Artocarpus teysmanii (A.teysmanii), and A. elasticus from Selangor[24-27]. An investigation of A. elasticus in 2019 also reported a new diprenylated flavone,artoflavone B (11)[27]. In 2010, two new prenylated flavones were reported from two different species collected from Sarawak[28,29].These flavones are named as artosimmin (12) from Artocarpus odoratissimus (A. odoratissimus) and hydroxyartocarpin (13) from the stem bark of Artocarpus altilis (A. altilis)[28,29]. Another three flavones isolated from A. altilis were identified as artocarpin (14),morusin (15), and cycloartocarpin A (16)[29]. Artochamin A (17),a prenylated pyranoflavone was isolated from the stem bark of Artocarpus kemando (A. kemando) also from Sarawak[30].

A thorough investigation on the leaves of A. fulvicortex from Terengganu gave a unique new flavone bearing two chromeno rings[22]. The structure was identified as 5-hydroxy-(6:7,3′:4′)-di(2,2-dimethylpyrano)flavone (18). Carpachromene (19) togetherwith cycloartocarpesin (20) and norartocarpetin (21) was isolated from A. fulvicortex[22]. Cycloartocarpesin (20) was also reported in a phytochemical study of A. elasticus from Selangor[23].

In 2015, two new and three known flavones were isolated from A. anisophyllus collected from Johor[20]. The new flavones were identified as 4′,5-dihydroxy-6,7-(2,2-dimethylpyrano)-2′-methoxy-8-γ,γ-dimethylallylflavone (22) and 3-hydroxycycloartocarpin(23) while the others are known as artocarpin (14), cycloartocarpin(24), and chaplashin (25)[20]. The following year, Abdullah et al.reported the isolation of artocarpin(14), 4′,5-dihydroxy-6,7-(2,2-dimethylpyrano)-2′-methoxy-8-γ,γ-dimethylallylflavone (22),and cycloheterophyllin (26) from A. lowii[18]. Whilst Arriffin et al.reported the isolation of 4′,5-dihydroxy-6,7-(2,2-dimethylpyrano)-2′-methoxy-8-γ,γ-dimethylallylflavone (22) from the bark of A. scortechinii in 2017[31]. Methoxycyclocommunol (27),cyclocommunol (28), and cudraflavone C (29) were present in the bark of Artocarpus integer var. silvestris (A. integer var. silvestris)from Pahang[32]. The structure of methoxycyclocommunol (27)was reported as a new derivative of cyclocommunol (28) due to the presence of a sharp peak indicating methoxy group inHNMR.

5.1.3. Flavanones

Two flavanones were reported for the first time from Artocarpus species characterized as 5,7-dihydroxy-4′-methoxy-8-prenylflavanone (30) and 5-hydroxy-7,8-(2,2-dimethylchromano)-4′-methoxyflavanone (31)[20,33]. In 2016, a phytochemical study on A. integer var. silvestris yielded heteroflavanone A (32) whilst two common flavanones named pinostrobin (33) and pinocembrin (34)were obtained from A. odoratissimus[32,34].

5.1.4. Flavanols

Flavanols are also referred to as dihydroflavonols. Shah et al.obtained a common flavanol named catechin (35) from the leaves of A. fulvicortex collected from Terengganu[35]. Arriffin et al. reported the isolation of two new dihydroflavonols named artoscortonol A(36) and artoscortonol B (37) from the leaves of A. scortechinii[36].The structures of all flavanones (30-34) and flavanols (35-37) are presented in Supplementary Figure 3.

5.1.5. Xanthones and stilbenoid

Several articles reported the isolation of artobiloxanthone (38),cycloartobiloxanthone (39), and artonol B (40) from the barks of A. scortechinii and A. teysmanii[24,25,31]. Two separate study by Ee et al. and Hashim et al. on A. kemando from Sarawak also isolated cycloartobiloxanthone (39) and artonol B (40)[30,37]. In addition, Ee et al. highlights another two xanthones named as artomandin (41),and artoindonesianin C (42) from A. kemando[30]. The first chemical investigation on the stem bark of A. obstusus in 2010 by Hashim et al. found two new xanthones named pyranocycloartobiloxanthone A (43) and dihydroartoindonesianin C (44)[38]. Afterwards, Hashim et al. reported the isolation of pyranocycloartobiloxanthone B(45) from A. obstusus and dihydroartoindonesianin C (44) from A.kemando[37,39].

In 2015, Lathiff et al. obtained pyranocycloartobiloxanthone A(43) from a rare Artocarpus species identified as A. anisophyllus[20].The following year, a known xanthone called artonin F (46)was reported from A. integer var. silvestris from Pahang whereas the investigation on the stem bark of A. altilis yielded two known xanthones, cycloartobiloxanthone (39) and artoindonesianin Ⅴ (47)[29,32]. An extensive investigation on A. elasticus in 2016 reported a new xanthone named elastixanthone (48) together with artobiloxanthone(38) and cycloartobiloxanthone (39)[26]. A recent investigation on A. elasticus in 2019 also reported the isolation of artobiloxanthone(38) and cycloartobiloxanthone (39), elastixanthone (48) as well as artoindonesianin P (49)[27]. Isolation of a common stilbenoid,oxyresveratrol (50) was reported from A. scortechinii and A.fulvicortex[31,35]. The structures of xanthones and stilbenoid (38-50) are presented in Supplementary Figure 4.

5.2. Other types of secondary metabolites

Isolation of friedelin (51), lupeol (52), and lupeol-3-acetate(53) was reported from separate study on A. fulvicortex from Terengganu[22,35]. A recent study showed A. odoratissimus roots contained two terpenoids, α and β amyrin acetate (54, 55)[34]. The structures can be distinguished from proton NMR and by comparison with literature. Traxateryl acetate (56) was also isolated from the stem bark and the roots of A. odoratissimus together with hexyl dodecanoate(57)[28,34]. Two common sterols, β-sitosterol (58) and stigmasterol(59) were reported from A. kemando and A. odoratissimus[29,34].Phytochemical studies on the stem bark of A. kemando from Sarawak yielded 6,7-dimethoxycoumarin (60) and aurantiamide benzoate(61). Aurantiamide benzoate (61) was reported as the first dipeptide isolated from genus Artocarpus. It was crystallized from chloroform extracts of A. kemando’s stem bark after a series of purification processes[37]. Structures of other secondary metabolites are shown in Supplementary Figure 5.

6. Pharmacological activities

The Artocarpus species have been exploited in various countries and revealed the medicinal variation possibility. As noted earlier, the most common ethnomedicinal usage was to treat wounds and ulcers as well as some skin problems. Extensive literature reported different pharmacological tests involved with the extracts and the isolated phytochemicals which exhibited anti-inflammatory, antioxidant,antimicrobial, gastroprotective, cytotoxic, anti-proliferative activities and acted as selective enzymes inhibitors. Qualitative and quantitative phytochemical screening of the Artocarpus extracts revealed their high phenolic content[40-45].

6.1. Antioxidant activities

Several reports have revealed the positive correlation between high phenolic content and the antioxidant activities of the crude extracts and fractions[40,42-45]. Antioxidant activity for isolated compounds also had been reported. 2′,4′-Dihydroxy-4-methoxy-3′-prenyldihydrochalcone (1), isobavachalcone (3)and 4-hydroxyonchocarpin (4) from A. lowii showed strong free radical scavenging activities against 2,2′-diphenyl-1-picrylhydrazyl(DPPH) with 50% inhibition (scavenging) concentrations (IC)of 0.03-0.24 mM using electron spin resonance spectrometry[17].Ferric reducing antioxidant power assay (FRAP), 2,2′-azinobis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and DPPH scavenging assays for all the isolates, 2′,4′-dihydroxy-4-methoxy-3′-prenyldihydrochalcone (1), 2′,4′-dihydroxy-3,4-(2″,2″-dimethylchromeno)-3′-prenyldihydrochalcone (2), isobavachalcone (3),4-hydroxyonchocarpin (4), artocarpin (14), and cycloheterophyllin(26) from A. lowii were also conducted. Cycloheterophyllin(26) gave promising results compared with standards, butylated hydroxyanisole (BHA) with 50% scavenging concentration(SC) values of 0.320 mM (BHA=0.554 mM) (ABTS), 0.10 mM(BHA=0.082 mM) (DPPH) and (4.70±0.09) [Trolox=(2.8±0.09)]FRAP equivalent[19]. New chalcones, elastichalcones A-B (8-9)and cycloartocarpesin (20) from A. elasticus were tested using Thin Layer Chromaography (TLC) bioautography method for DPPH scavenging activity. Elastichalcone B (9) and cycloartocarpesin (20)showed colour changes and further evaluation using 96-wells with a microplate photometer supported the TLC results with ICvalues of 11.30 and 11.89 μg/mL respectively[23].Pyranocycloartobiloxanthone A (43) was obtained from Artocarpus obstusus for the first time together with dihydroartoindonesianin C (44) and pyranocycloartobiloxanthone B (45). Although they have similar backbones, only pyranocycloartobiloxanthone A (43)showed promising results against DPPH radical with ICof 2.0 μg/mL while the other xanthones were considered inactive with ICmore than 500 μg/mL[38,39]. Isobavachalcone (3), artocarpin(14), 4′,5-dihydroxy-6,7-(2,2-dimethylpyrano)-2′-methoxy-8-γ,γ-dimethylallylflavone (22), 5,7-dihydroxy-4′-methoxy-8-prenylflavanone (30), 5-hydroxy-7,8-(2,2-dimethylchromano)-4′-methoxyflavanone (31) and pyranocycloartobiloxanthone A (43)from A. anisophyllus were tested using DPPH scavenging assay with a microplate photometer. Pyranocycloartobiloxanthone A (43)demonstrated strong antioxidant activity with SCof 20.2 μg/mL comparable with the positive control, BHA (SC=17.5 μg/mL)[20].The structure activity relationship between flavonoids artosimmin(12), cycloartobiloxanthone (39), artonol B (40), artomandin (41),artoindonesinin C (42) and extracts of A. odoratissimus and A.kemando was evaluated using DPPH radical scavenging assay. All extracts of A. odoratissimus exhibited weak inhibition activity (＞120 μg/mL) compared with A. kemando (＜55 μg/mL). Artomandin (41)and artosimmin (12) from A. kemando exhibited the highest potential in DPPH radical scavenging assay with ICof 38.0 and 32.1 μg/mL respectively[46]. The antioxidant capacities of Artocarpus secondary metabolites and extracts might lead to alleviation of diabetes mellitus and link to inhibition of tumour or cancer cell with potential antiproliferative activities[47,48].

6.2. Anti-inflammatory activity

The anti-inflammatory activity of 2′,4′-dihydroxy-4-methoxy-3′-prenyldihydrochalcone (1), isobavachalcone (3),4-hydroxyonchocarpin (4), and cycloheterophyllin (26) from A. lowii was investigated using cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) screening kit. Isobavachalcone (3)was found to possess potent anti-inflammatory activity via COX-2 mechanism (IC=0.95 μM). However, no activities were shown by other compounds towards COX-2 and 15-LOX[49]. In 2017, seven flavonoids i.e. 2′,4′-dihydroxy-4-methoxy-3′-prenyldihydrochalcone(1), isobavachalcone (3), artonin E (10), artocarpin (14),4′,5-dihydroxy-6,7-(2,2-dimethylpyrano)-2′-methoxy-8-γ,γ-dimethylallylflavone (22), cycloheterophyllin (26) and oxyresveratrol (50) from several Artocarpus species were investigated on inhibitory effect against the production of prostaglandin E(PGE) in human plasma. The level of PGEin plasma was determined using radioimmunoassay technique. Artocarpin (14)showed the highest inhibition of 68.1% followed by artonin E(10) (66.8%) compared with the positive control, indomethacin(79.2%). 2′,4′-Dihydroxy-4-methoxy-3′-prenyldihydrochalcone(1), artonin E (10), artocarpin (14), and 4′,5-dihydroxy-6,7-(2,2-dimethylpyrano)-2′-methoxy-8-γ,γ-dimethylallylflavone (22) were the most potent inhibitors with ICvalues of 8.99 μM, 8.98 μM,11.66 μM, and 7.04 μM, respectively (indomethacin: IC=2.27 μM). These compounds reduced PGEproduction in human blood which directly inhibited COX-2 enzymatic activity[50]. Isolated compounds methoxycyclocommunol (27), cyclocommunol(28), cudraflavone C (29), heteroflavanone A (32), and artonin F (46) from A. integer var. silvestris were tested for their antiinflammatory activity using 15-LOX screening kit and inhibitory effects on production of PGEin whole blood. All compounds showed weak inhibition against 15-LOX even at a concentration of 100 μM. Only methoxycyclocommunol (27), cudraflavone C(29), heteroflavanone A (32), and artonin F (46) were screened for inhibitory effects on production of PGEin whole blood using radioimmunoassay methods. All compounds except artonin F (46)showed more than 55% inhibition which then proceeded to serial dilution method to determine the ICvalue. Cudraflavone C (29)showed the most potent COX-2 inhibition on PGEwith ICof 0.07 μM which showed lower concentration needed for 50% inhibition compared with the positive control, indomethacin (IC=0.2 μM).Methoxycyclocommunol (27) and heteroflavanone A (32) also showed remarkable COX-2 inhibition on PGEwith ICvalues of 4.3 and 0.8 μM, respectively[32]. These results indicated that isolated flavonoids from Artocarpus do not respond towards 15-LOX mechanisms but act as selective inhibitors through COX-2 pathway.

6.3. Antimicrobial activity

Pyranocycloartobiloxanthone A (43), dihydroartoindonesianin C(44), and pyranocycloartobiloxanthone B (45) were screened for their antimicrobial properties using disc diffusion method. Only pyranocycloartobiloxanthone A (43) showed inhibition against most of the bacteria and fungi tested. Among all the microbes,pyranocycloartobiloxanthone A (43) showed the most promising result against methicillin resistant Staphylococcus aureus (S. aureus)(MRSA) with a 20 mm inhibition zone. Dihydroartoindonesianin C (44), and pyranocycloartobiloxanthone B (45) were found to be inactive[39]. Pyranocycloartobiloxanthone A (43) was also tested against two strains of Helicobacter pylori, NCTC 11637 (ATCC 43504) and J99 (ATCC 700824) with MIC values of ＞ 250 μg/mL and 62.5 μg/mL, respectively. Helicobacter pylori is a bacterium that can cause ulcers in the stomach[51].

Crude extracts and ten isolated flavonoids, 2′,4′-dihydroxy-4-methoxy-3′-prenyldihydrochalcone (1), 2′,4′-dihydroxy-3,4-(2″,2″-dimethylchromeno)-3′-prenyldihydrochalcone (2), isobavachalcone(3), 4-hydroxyonchocarpin (4), artocarpin (14), 4′,5-dihydroxy-6,7-(2,2-dimethylpyrano)-2′-methoxy-8-γ,γ-dimethylallylflavone(22), cycloheterophyllin (26), 5,7-dihydroxy-4′-methoxy-8-prenylflavanone (30), 5-hydroxy-7,8-(2,2-dimethylchromano)-4′-methoxyflavanone (31) and pyranocycloartobiloxanthone A (43)from A. lowii and A. anisophyllus were screened for antimicrobial activities against four bacteria (Bacillus subtilis, S. aureus, Escherichia coli, Pseudomonas putida) and two fungi (Candida albicans,Candida glabrata) via disc diffusion method and determination of minimum inhibitory concentration as well as minimum microbicidal concentration. The crude extracts showed inhibition against Grampositive bacteria but a negative response toward fungi. Artocarpin(14) showed the most promising result as an antimicrobial agent with more than 11 mm inhibition zone and a minimum microbicidal concentration value of 0.45 mg/mL[19].

In 2015, ultrastructural changes of S. aureus were compared against artonin E (10) and streptomycin (positive control) using two methods, standard antimicrobial technique, and transmission electron microscopy. The minimum inhibitory concentration of 3.9 μg/mL and minimum microbicidal concentration of 7.81 μg/mL against S. aureus proved that artonin E (10) is active against Grampositive bacteria. In addition, the transmission electron microscope images of S. aureus before and after artonin E (10) treatment were shown and the original shape, cocci colonies of grape shape walls were missing, shredded and broken which led to distorted shape and focally thickened outer membrane indicating severe damage[52].

6.4. Tyrosinase inhibitory activity

Preliminary screening of pyranocycloartobiloxanthone A (43) from Artocarpus obtusus showed significant tyrosinase inhibitory activity with 80% inhibition comparable to kojic acid with 96% inhibition[39].Further investigation by Lathiff et al. proved that aside from acting as a potent antioxidant, pyranocycloartobiloxanthone A (43) also acted as a tyrosinase inhibitor with ICof 60.5 μg/mL (kojic acid = 31.2 μg/mL)[20]. As expected, the ethyl acetate extract of A. anisophyllus heartwood where the compound was isolated exhibited a low ICvalue (155.4 μg/mL). Other isolated flavonoids i.e. isobavachalcone(3), hydroxyartocarpin (13), artocarpin (14) and 4′,5-dihydroxy-6,7-(2,2-dimethylpyrano)-2′-methoxy-8-γ,γ-dimethylallylflavone(22) were also evaluated for their inhibitory effect against tyrosinase enzyme in vitro with ICvalues of more than 200 μg/mL[20].Cycloheterophyllin (26) from A. lowii demonstrated significant tyrosinase inhibitory activity against mushroom tyrosinase with ICof 52.5 μg/mL comparable with the positive control, kojic acid (IC=31.2 μg/mL). Other flavonoids 2′,4′-dihydroxy-4-methoxy-3′-prenyldihydrochalcone (1), 2′,4′-dihydroxy-3,4-(2″,2″-dimethylchromeno)-3-prenyldihydrochalcone (2), isobavachalcone(3), 4-hydroxyonchocarpin (4), artocarpin (14), and 4′,5-dihydroxy-6,7-(2,2-dimethylpyrano)-2′-methoxy-8-γ,γ-dimethylallylflavone(22) were also tested but found inactive[53].

6.5. Cholinesterase inhibitory activity

Isobavachalcone (3), 5,7-dihydroxy-4′-methoxy-8-prenylflavanone (30) and 5-hydroxy-7,8-(2,2-dimethylchromano)-4′-methoxyflavanone (31) from A. anisophyllus were selected for in silico bioactivity analysis. 5,7-Dihydroxy-4′-methoxy-8-prenylflavanone (30) was found nontoxic in absorption, digestion,metabolism, and excretion study. 5,7-Dihydroxy-4′-methoxy-8-prenylflavanone (30) also followed the drug-likeness properties in Molsoft described by Lipinski Rule of 5 (RO5) for orally administered drugs. In this study, acetylcholinesterase (AChE) was chosen as target while 5,7-dihydroxy-4′-methoxy-8-prenylflavanone(30) as ligand. Molecular docking was performed between ligand and target along with known inhibitors and drug molecules available on the market. The docking score of ligand-target binding complex(-13.576 2) was more significant than phase 4 drugs but lower than donepezil (-15.497 4) and some other known inhibitors. The ICvalue for 5,7-dihydroxy-4′-methoxy-8-prenylflavanone (30)was 1 659 nM against AChE in QSAR analysis. In vitro experiment was done to validate the in silico result using TLC bioautographic method and 5,7-dihydroxy-4′-methoxy-8-prenylflavanone (30) showed potential as an AChE inhibitor with a detection limit of 125 μg/mL[33].

Dichloromethane and methanol extracts of A. fulvicortex heartwoods demonstrated AChE inhibitory activity with a detection limit of 2 mg/mL. Catechin (35) and oxyresveratrol (50) from A.fulvicortex exhibited moderate AChE inhibitory activity using TLC bioautographic method and microplate assay. Oxyresveratrol (50)acted as a potent inhibitor with ICvalue of 6.25 mM comparable to galanthamine as a positive control[35]. In 2019, cholinesterase inhibition screening of methanol extracts of A. altilis and A. integer leaves against AChE and BChE at 200 μg/mL was done with physostigmine as the positive control. Both species showed inhibition percentage of more than 80%. Further investigation revealed acidic fraction (via acid-base fractionation of methanol extract) of A. altilis leaves showed higher inhibition compared to ethyl actetate fraction(via liquid-liquid fractionation of methanol extract)[54].

6.6. Alpha glucosidase activity

Six compounds from A. elasticus were screened using alpha glucosidase-UV assay. Artonin E (10), artoflavone B (11) and four dihydrobenzoxanthone known as artobiloxanthone (38),cycloartobiloxanthone (39), elastixanthone (48) and artoindonesianin P (49) showed promising results as alpha glucosidase inhibitors with ICbetween 7.6-25.4 μM. Overall, all compounds showed dose dependent inhibition of enzyme. A detailed kinetic analysis on the inhibition of artobiloxanthone (38), cycloartobiloxanthone(39), elastixanthone (48) and artoindonesianin P (49) was carried out using double reciprocal plots. These analyses determined the kinetic profile of elastixanthone (48) with ICvalue of 7.6 μM as a slow binding inhibitor due to the residual activity of the enzyme which decreases as a function of preincubation time. Molecular docking was also conducted between Saccharomyces cerevisiae alpha-glucosidase and the xanthones as ligand. The docking results revealed that all compounds have similar binding confirmations stabilized by interactions[27].

6.7. Cytotoxicity

Cytotoxicity in natural product is an important aspect to be measured as it requires to produce effects only on targeted cells without harming the host[55]. Artosimmin (12) and artomandin(41) exhibited strong inhibition activity against HL-60 human promyelocytic leukemia with ICof 1.1 and 2.4 μg/mL, respectively,and against MCF-7 human breast adenocarcinoma cancer cell with ICof 3.4 and 3.1 μg/mL, respectively[28,30]. The cytotoxicity of A. odoratissimus ethanol fruit extract was tested against human liver cancer cells (HepG2), human colon cancer cells (HT-29), and human ovarian cancer cells (Caov3) and was found inactive towards all tested cells[41]. A. altilis methanol pulp extract showed some toxicity against HeLa cells with ICof 50 μg/mL. Cell proliferation and viability decreased as the concentration of the A. altilis methanol pulp extract increased[56].

Pyranocyloartobiloxanthone A (43) exhibited strong antiproliferative activity against K562 human chronic myeloid leukemia cell with ICof 0.5 μg/mL and moderate inhibition against HL-60 human promyelocytic leukemia cell with ICof 2.0 μg/mL and MCF7 positive breast cancer cell with ICof 5.0 μg/mL in MTT assay[57]. Pyranocycloartobiloxanthone A (43) showed significant gastroprotective efficacy using ethanol-induced ulcer model in rats.The 50% lethal dosage (LD) value of pyranocycloartobiloxanthone A (43) was more than 300 mg/kg in acute toxicity analysis. The possible side effect to other organs was also analyzed using liver function test. This study revealed that pre-treatment with pyranocycloartobiloxanthone A (43) significantly protects and reduces gastric mucosa from ethanol-induced gastric lesions as well as restores the depleted gluthione, non-protein sulfhydryl compound and nitric oxide levels in gastric homogenate[51].

Several pieces of research were conducted to investigate the cytotoxicity and inhibitory mechanism of artonin E (10) towards ovarian and breast cancer cells. Rahman et al. reported that artonin E (10) induced antiproliferative effect that led to S phase cell cycle arrest in a time-dependent manner and apoptosis by dysregulating mitochondrial pathways in SKOV-3 ovarian cancer cells[58]. Antiproliferative effects of artonin E (10) on various cell lines were evaluated using MTT assay. The ICvalue for human ovarian adenocarcinoma cells (SKOV-3) was dramatically decreased after 24 h, comparable to the positive control, carboplatin, and paclitaxel. However, the normal human ovarian surface epithelial cells (T1074) showed more resistance towards artonin E. Artonin E also showed potential to inhibit aggressive triple-negative breast cancer cell (MDA-MB-231) by effectively reducing the apoptosis evading capacity, causing a half-maximal growth inhibition at low concentrations (14.3, 13.9 and 9.8 μM) after 24, 48 and 72 h respectively[59]. Furthermore, artonin E (10) helped in delaying quadruple tumor growth by more than 5 days compared to the untreated control group in female mice bearing 4T1 mammary tumors[60].

An in vitro study demonstrated jacalin, a lectin purified from protein extracts of Artocarpus heterophyllus seeds inhibited the viability of cancer cell MCF7 and H1299. The cancer cell viability was significantly decreased within 24 h upon treatment with purified and standard jacalin. The difference of 10% of cell viability between the purified jacalin and the extracts showed that it is necessary to purify the protein extract. At the highest concentration (10 μL), the purified and standard jacalin showed almost equal proliferation activity with only 0.98% difference[61].

6.8. Other pharmacological activities

Isolated compounds, 2′,4′-dihydroxy-4-methoxy-3′-prenyldihydrochalcone (1), isobavachalcone (3), artonin E (10),cycloheterophyllin (26), artobiloxanthone (38), cycloartobiloxanthone(39) and artonol B (40) from A. lowii, A. scortechinii, and A. teysmanii were investigated for their ability to inhibit arachidonic acid, collagen,and adenosine diphosphate-induced platelet aggregation in human whole blood. Cycloheterophyllin (26) inhibited arachidonic acid with ICof 100.9 μM and showed strong inhibition against adenosine diphosphate-induced aggregation with ICof 57.1 μM[62].

7. Conclusions and recommendations

This review highlights the phenolic compounds from selected Artocarpus in Malaysia, as well as their pharmacological activities.To date, 61 distinct compounds had been isolated from Malaysia’s Artocarpus and 18 were reported as new ones. Although there are 32 Artocarpus species identified in Malaysia, the published articles showed that research in Malaysia focuses on twelve Artocarpus species i.e. A. altilis, A. anisophyllus, A. elasticus, A. fulvicortex,Artocarpus heterophyllus, A. integer var. silvestris, A. kemando, A.lowii, Artocarpus obtusus, A. odoratissimus, A. scortechinii and A.teysmanii. Based on literature review, A. altilis is the most widely utilized Artocarpus species. Data gathered highlights the potential of Artocarpus as an important source of secondary metabolites to inhibit a certain enzyme, and act as antioxidant, antimicrobial, antiinflammatory as well as cytotoxic and gastroprotective agents.

Further research such as in silico and in vivo assay is recommended for better understanding on how the isolated natural products work. Only two in silico studies of Artocarpus from Malaysia were conducted and valuable data were gathered[27,33]. Pro-oxidant activity of isolated compounds in the presence of copper ions may also be explored as there are evidence associated with anticancer activity[63]. Furthermore, other parts of the plant such as flower can also be explored as there are recent articles that highlighted the flower of Artocarpus lakoocha and Artocarpus heterophyllus as a source of bioactive compounds[55].

Conflict of interest statement

We declare that there is no conflict of interest.

Acknowledgments

The authors would like to thank the Ministry of Higher Education for the financial support under (Q.J130000.2554.21H57) and the Faculty of Science, Universiti Teknologi Malaysia for sources and research facilities. Lathiff SMA would like to acknowledge Zamalah Universiti Teknologi Malaysia for providing the scholarship.

Funding

This work is supported by the Ministry of Higher Education(Q.J130000.2554.21H57).

Authors’ contributions

SMAL and SJ created the concept and designed the structural and intellectual content. SMAL as the main author involved in the preparation and review of the manuscript. Both SMAL and SJ also involved in the final version of the manuscript. While SMAL and NMA contributed to literature search, data and statistical analysis as well as manuscript editing. SJ as a corresponding author also acted as a guarantor and supervised the project.