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. 2022 Mar 13;27(6):1863. doi: 10.3390/molecules27061863

Phytochemical Insights into Ficus sur Extracts and Their Biological Activity

Elwira Sieniawska 1,*,†, Łukasz Świątek 2,*,†, Kouadio Ibrahime Sinan 3, Gokhan Zengin 3, Anastazja Boguszewska 2, Małgorzata Polz-Dacewicz 2, Nabeelah Bibi Sadeer 4, Ouattara Katinan Etienne 5, Mohamad Fawzi Mahomoodally 4
Editors: Vincenzo De Feo, Mohamed L Ashour, Nawal M Al Musayeib, Fadia S Youssef
PMCID: PMC8949149  PMID: 35335228

Abstract

This study focused on the biological evaluation and chemical characterisation of Ficus sur Forssk. (F. sur) (Family: Moraceae). The methanolic and aqueous extracts’ phytochemical profile, antioxidant, and enzyme inhibitory properties were investigated. The aqueous stem bark extract yielded the highest phenolic content (115.51 ± 1.60 mg gallic acid equivalent/g extract), while the methanolic leaves extract possessed the highest flavonoid content (27.47 ± 0.28 mg Rutin equivalent/g extract). In total, 118 compounds were identified in the tested extracts. The methanolic stem bark extract exhibited the most potent radical scavenging potential against 2,2-diphenyl-1 picrylhydrazyl and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (475.79 ± 6.83 and 804.31 ± 4.52 mg Trolox equivalent/g extract, respectively) and the highest reducing Cu2+ capacity (937.86 ± 14.44 mg Trolox equivalent/g extract). The methanolic stem bark extract substantially depressed tyrosinase (69.84 ± 0.35 mg kojic acid equivalent/g extract), α-amylase (0.77 ± 0.01 mmol acarbose equivalent/g extract), acetylcholinesterase and butyrylcholinesterase (2.91 ± 0.07 and 6.56 ± 0.34 mg galantamine equivalent/g extract, respectively) enzymes. F. sur extracts were tested for anticancer properties and antiviral activity towards human herpes virus type 1 (HHV-1). Stem bark infusion and methanolic extract showed antineoplastic activity against cervical adenocarcinoma and colon cancer cell lines, whereas leaf methanolic extract exerted moderate antiviral activity towards HHV-1. This investigation yielded important scientific data on F. sur which might be used to generate innovative phytopharmaceuticals.

Keywords: Ficus, natural products, fig, antioxidant, enzymes, phytochemistry, LC-MS, anticancer, natural antivirals

1. Introduction

For millennia, humans have centred their lives on plants in an effort to maintain good health and treat common ailments. Even though the usage of plants was based simply on people’s intuitive understanding, owing to a lack of suitable techniques to show plants’ therapeutic potential, humans have accepted the use of many medicinal plants and included them in contemporary pharmacotherapy [1]. The Royal Botanic Gardens at Kew’s Bob Allkin recognised around 28,000 plant species as medicinal plants [2]. Since the eureka moment of the discovery of Taxol, the blockbuster anti-cancer medicine produced from the Pacific yew tree, plants have demonstrated their healing ability [3]. Since then, medicinal plants have quickly captured the interest of scientists, resulting in the increased screening of medicinal plants and the use of health-promoting plant extracts in nutrition.

In line with the present worldwide trend, the medicinal plant that this study sought to investigate was Ficus sur Forssk. (F. sur) (Family: Moraceae). The genus Ficus comprises more than 800 species and is generally distributed in tropical and sub-tropical areas [4]. Morphologically, it is a tree that can grow up to 25–30 m tall, with leafy twigs 2–5 mm thick, puberulous, hirtellous, tomentose or hirsute to glabrescent, with the periderm typically not flaking off when dry [5]. F. sur, with the common names Cape fig and broom cluster fig, is used to treat a variety of ailments in many countries. Its leaves and roots are used to cure leukoderma, leprosy, wounds, oedema, respiratory problems, diarrhoea, sexually transmitted illnesses, tuberculosis, anaemia, epilepsy, rickets, dysentery, male infertility, and gonorrhoea in Sudan and Nigeria [6]. According to ethnobotanical research, F. sur is also used to cure swellings [7]. It has long been used in South Africa and other nations to treat renal disorders and as a natural diuretic product [8,9]. In Ethiopia, pulverized fresh F. sur leaves combined with water were administered orally as a traditional medicine for urine retention, effectively alleviating the condition by boosting urine production. There is also a traditional belief that the root of this plant may be utilized to treat bladder diseases [10,11]. Despite the reported beneficial effects of members of the genus Ficus, several side effects (particularly when eating fruits) have been reported. These include stomach problems, obstructions in the intestine and liver damage [8]. It is necessary not to exceed the recommended dose for the fruits.

The findings of Ayele and co-workers are consistent with the traditional usage of F. sur as a diuretic agent. The crude leaf extracts enhanced urine excretion and urinary electrolyte concentrations in a dose-dependent manner [12]. The results of another study indicated that an ethanol extract of F. sur has a substantial anticonvulsant effect, validating the traditional use of the plant in the treatment of epilepsies; processes may entail interaction with GABAergic, glycinergic, serotonergic, and glutaminergic system components [13]. The purpose of another study was to see how feeding a mixture of varying amounts of F. sur fruits and ground maize grain affected intake, digestibility, growth, and blood profile in Yorkshire pigs [14]. The findings demonstrated that the health of the pigs was better when fed with F. sur fruits as creatinine and cholesterol concentrations were lower.

There are reports describing the antiviral potential of different species of Ficus. Ethanolic extracts from F. benjamina leaves inhibited human herpes virus type 1 (HHV-1, HSV-1) and type 2 (HHV-2, HSV-2), and varicella-zoster virus (HHV-3, VZV), while fruit extracts were active only against HHV-3 [15]. F. carica latex inhibited caprine herpes virus-1 (CpHV-1) replication in MDBK cells [16], as well as HHV-1, echovirus type 11 (ECV-11) and adenovirus (ADV) replication in VERO cells [17]. Leaf methanol extract from F. septica impeded dengue virus (DENV) replication in various infected cell types [18], and F. religiosa bark extracts showed activity against human rhinovirus (HRV) and human respiratory syncytial virus (RSV) [19], and HHV-2 [20]. Recently, ethanol extract of Ficus fistulosa leaves was reported to show anti-HIV activity [21].

Our aims with this study were to screen methanolic and aqueous leaves and stem bark extracts of F. sur for antioxidant and anti-enzymatic activities. Additionally, since the absence of detailed characterisation can markedly limit our understanding of their biological activities, the extracts were subjected to detailed phytochemical profiling. The search for new cholinesterase inhibitors (acetyl- and butyryl-cholinesterase) and carbohydrate digesting inhibitors (α-amylase and α-glucosidase) is now underway and our work has evaluated several extracts of F. sur for probable anti-cholinesterase and antidiabetic activities. Since multiple Ficus species were shown to possess antiviral activity, we have undertaken the attempt to evaluate the anti-HHV-1 activity of extracts obtained from Ficus sur. Furthermore, we have evaluated the anticancer potential of this plant species against cervical adenocarcinoma and colon cancer cell lines. We hope that the information offered here will assist in bridging a research gap and, as a result, open up new research opportunities, notably in the production of medicinal bioproducts.

2. Results and Discussion

2.1. Bioactive Compounds

The polarity of the solute of interest was considered in choosing the solvents used to extract bioactive compounds from plants because a solute with equivalent polarity to the solvent will be sufficiently dissolved according to the law of similarity and intermiscibility [22,23]. In this study, polyphenolic compounds, such as phenolic compounds and flavonoids, were quantified from the methanolic and aqueous extracts of F. sur. The results are presented in Table 1.

Table 1.

Total phenolic and flavonoid contents of Ficus sur extracts.

Parts Solvents TPC (mg GAE/g) TFC (mg RE/g)
Leaves MeOH 58.46 ± 0.28 c 27.47 ± 0.28 a
Infusion 51.77 ± 0.77 d 16.65 ± 0.18 b
Stem barks MeOH 109.79 ± 2.19 b 2.54 ± 0.10 c
Infusion 115.51 ± 1.60 a 1.13 ± 0.11 d
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Values are reported as mean ± SD of three parallel measurements. GAE: Gallic acid equivalents; RE: Rutin equivalents. Different letters in the same column indicate significant differences in the teste extracts (p < 0.05).

Among the samples studied, the aqueous extract obtained from the stem bark yielded the highest amount of phenolics (115.51 ± 1.60 mg GAE/g), while the methanolic extract prepared from leaves had the highest flavonoid content (27.47 ± 0.28 mg RE/g). LC-ESI-QTOF-MS/MS analysis enabled the chemical characterization of all studied extracts. In total, 118 compounds were described (Table 2, Figure 1). It was observed that the leaf extracts contained more compounds compared to the stem bark extracts. Phenolic acids (such as quinic, citric, dihydroxybenzoic, 3-O-caffeoylquinic, and 5-O-caffeoylquinic acid), quercetin glycosides (quercetin-O-di-rhamnosyl-glucoside/galactoside, quercetin-O-glucoside, quercetin-O-pentoside (arabinoside), quercetin-O-glucuronide), and fatty acids (hydroxy octadecatrienoic acid, palmitic acid derivative) were present in almost all extracts. The methanolic extract from leaves contained mainly phenolic acids and their derivatives, esters of phenolic acids and flavonoids, and flavonoid glycosides (esters of kaempferol and quercetin). Hydroxycoumarin and methyl gallate were present only in this extract. Hydroxycaffeoylquinic, glucogallic, 2-isopropylmalic, tartaric, coumaric, ferulic acids and their esters were characteristic for leaf infusion. The methanolic extract from the stem bark was abundant in tannins, represented by catechins and procyanidins. In the stem bark infusion, apigenin, luteolin, kaempferol, quercetin and their conjugates with one or more sugar moieties dominated. The majority of the detected secondary metabolites were typical for previously studied Ficus species: F. lyrata, F. benghalensis, F. benjamina, F. mysorensis, F. afzelii, F. pyriformis, F. racemose, F. lutea, F. auriculata, F. trigonata, F. spragueana, F. microcarpa var. nitida; F. virens and F. religiosa for which the presence of flavonoids, flavonolignans, anthocyanins and hydroxycinnamic acids derivatives was reported [24,25].

Table 2.

Compounds identified in the studied extracts.

Comp. No Tentative Identification R Time Molecular Mass [M − H]− Fragment Ions (m/z) Extracts
1 Quinic acid 1.91 192.0507 191.0507 173.0464; 111.0437; 93.0318; 85.0262 1,2,3
2 Citric acid 2.33 192.0180 191.0180 111.0035; 87.0052 1,2,3,4
3 Caffeic acid derivative 3.40 242.0302 241.0302 179.0273; 153.0497; 135.0406; 123.0407; 109.0230 4
4 Quinic acid derivative 3.46 534.1621 533.1621 337.0845; 191.0508 2
5 Quinic acid derivative 4.04 406.0968 405.0968 213.0351; 191.0511 4
6 4-Hydroxy-2-(hydroxymethyl)benzoic acid 4.09 168.0307 167.0307 149.0234; 123.0429 3
7 Dihydroxybenzoic acid glucoside derivative 4.13 532.0929 531.0929 353.0781; 315.0642; 153.0155; 96.9570 2
8 Quinic acid derivative 4.22 470.0574 469.0574 435.1422; 371.0962; 191.0423 2
9 Hydroxycaffeoyl-quinic acid 4.76 372.0900 371.0900 353.0840; 197.0360; 191.0533; 179.0312; 173.0431;135.0409 2
10 Glucogallic acid/Glucosyl gallate 6.32 332.0607 331.0607 169.0124; 151.0003; 125.0211 2
11 Dihydroxybenzoic acid glucoside derivative 6.49 436.0075 435.0075 315.0710; 153.0056 1
12 Dihydro-caffeoyl-quinic acid 6.56 356.0959 355.0959 191.0522; 181.0167; 173.0451; 137.0164; 111.0044 2
13 Hydroxybenzoic acid derivative 6.77 432.1224 431.1124 137.0243; 93.0383 3
14 Caffeoyl-hydroxybenzoic acid 7.23 300.0717 299.07117 239.0562; 179.0356; 137.0228 4
15 Dihydroxybenzoic acid glucoside isomer 1 7.487 316.0628 315.0628 153.0134; 152.0105; 108.0213 1,2
16 Dihydroxybenzoic acid 7.59 154.0143 153.0143 109.0302; 108.0225 1,2,3,4
17 Coumaric acid-hexoside-pentoside 8.48 458.0892 457.0892 325.0865; 163.0347 2
18 Dihydroxybenzoic acid glucoside isomer 2 8.51 316.0660 315.0660 153.0147; 109.0258 2
19 3-Hydroxy-4-methoxymandelate glucoside 8.86 360.0924 359.0924 197.0449; 182.0215; 153.0557; 138.0321; 123.0129 3
20 Caffeic acid derivative hexoside 9.06 376.0601 375.0601; 341.1069; 213.0650; 201.0144; 179.0316; 135.0409 1
21 Quinic acid derivative 9.08 372.0868 371.0868 251.0544; 191.052; 167.0327 1
22 2-Isopropylmalic acid 9.19 176.0571 175.0571 157.0486; 115.0371; 85.0638 2
23 Hydroxybenzoic acid 9.29 138.0208 137.0208 108.0231 3, 4
24 Unidentified 9.39 376.1236 375.1236 312.0725; 169.0827; 151.0726 4
25 Hydroxybenzoic acid 4-O-glucoside 10.17 300.0669 299.0669 137.0203; 93.0315 1,2
26 3-O-Caffeoylquinic acid 10.36 354.0782 353.0782 191.0578; 179.0370; 161.0243; 135.0461 1,2,3
27 Dihydroxybenzoic acid glucoside isomer 3 10.69 316.0660 315.0660 153.0144; 109.0258 2
28 Caffeic acid glucoside 10.76 342.0825 341.0825 179.0357; 161.0246; 135.0457 4
29 Dihydroxybenzoic acid O-glucoside-pentoside 10.84 448.1382 447.1382 315.1063; 153.0548; 109.0301; 108.0249 3
30 Hydroxycoumarin 10.93 340.0715 339.0715 177.0178 1
31 Methyl gallate 11.02 184.0234 183.0234 168.0071; 124.0155; 78.0128 1
32 Hydroxybenzoic acid 11.13 138.0210 137.0210 109.0209; 108.0308; 93.0345 4
33 Glucogallic acid/Glucosyl gallate 11.50 332.0607 331.0607 169.0113;168.0047;125.0225 1,2,4
34 3-O-p-Coumaroylquinic acid 11.30 338.0840 337.0840 191.0540; 163.0384 1,2
35 Procyanidin B (dimer of (epi)catechin) 11.62 578.1270 577.1270 451.1080; 425.0892; 407.0834; 289.0734; 245.0811; 125.0239 3
36 Caffeic and coumaric acid derivative 12.20 542.1494 541.1494 523.1466; 475.1519; 361.0900; 235.0490; 215.0901; 179.0358; 163.0398; 137.0249 4
37 1-O-Coumaroylquinic acid 12.28 338.0840 337.0840 191.0509; 173.0417; 163.0356 1,2
38 Glucogallic acid tartaric ester 12.33 464.1040 463.1040 331.0608; 169.0147; 168.0037; 149.9937; 125.0212 3
39 Caffeic acid glucoside 12.34 342.0825 341.0825 179.0344; 161.0230; 135.0440 4
40 Gallic acid glucoside derivative 12.55 412.0173 411.0173 367.355; 331.0632; 240.9965; 169.0091; 125.0157 2
41 Caffeic acid derivative hexoside 12.63 542.1494 541.1494 379.0983; 179.0323; 161.0220; 135.0425 4
42 Methyl gallate hexoside-pentoside 12.70 448.1542 447.1542 345.1151; 183.0660; 168.0382; 161.0437 3
43 (Epi)gallocatechin 13.18 306.0612 305.0612 287.0562; 269.0489; 219.0678; 195.0310; 179.0321; 161.0246; 137.0237; 125. 0235 3
44 5-O-Caffeoylquinic acid 13.27 354.0811 353.0811 191.0521; 161.0214; 135.0406 1,2,3
45 Dihydroxycoumarin 13.47 178.0152 177.0152 161.0960; 133.0279; 105.0338 4
46 3-O-Feruloylquinic acid 13.66 368.0964 367.0964 193.0481; 173.0430; 134.0355 2
47 4-O-Caffeoylquinic acid 14.32 354.0811 353.0811 191.0516; 179.0306; 173.0412; 135.0414 2
48 Caffeic acid 14.41 180.0293 179.0293 135.0451 1,4
49 Coumaroyltartaric acid isomer 1 14.68 296.0404 295.0404 163.0357; 149.0051; 130.9957; 119.0460 2
50 Tartaric acid 14.94 150.0055 149.0055 130.9997; 102.9993; 87.0065 2
51 4-O-Methylgallocatechin 15.25 320.0763 319.0763 287.0497; 243.0251; 197.0451; 161.0242; 125.0233 3
52 Caffeic and hydroxycinnamic acid derivative 15.39 380.0995 379.0995 369.0971; 251.0590; 217.0658; 179.0345; 161.0261; 135.0426 4
53 Coumaric acid hexoside derivative 15.49 442.0969 441.0969 325.0912; 163.0378; 119.0507 2
54 Coumaric acid 15.76 164.0361 163.0361 119.0483 2
55 Coumaroyltartaric acid isomer 2 15.82 296.0404 295.0404 163.0363; 149.0056; 130.9944; 119.0472 2
56 B-type procyanidin trimer 16.03 866.1873 865.1873 739.1731; 713.1525; 577.1396; 425.0996; 287.0524; 245.0479; 125.0216 3
57 Caffeic acid pentoside 16.15 312.0340 311.0340 179.0036; 135.0380 2
58 4-O-p-Coumaroylquinic acid 16.33 338.0871 337.0871 191.0520; 173.0423; 163.0363 1,2
59 Procyanidin B (dimer of (epi)catechin) 16.54 578.1226 577.1226 451.0947; 425.0842; 407.0791; 289.0774; 245.0500 1,3
60 Caffeic acid and hydroxycoumarin derivative 16.93 458.1282 457.1282 383.0989; 221.0481; 179.0362; 161.0255; 135.0433; 133.0275; 117.0335 4
61 (Epi)catechin derivative 17.11 326.0425 325.0425 289.0667; 245.0790; 205.0449; 125.0275 3
62 Sinapoyl-ferulate 17.22 400.0876 399.0876 223.0469; 205.0374; 193.0429; 129.0150; 111.0050; 85.0271 2
63 (Epi)catechin 17.26 290.0637 289.0637 245.0785; 205.0476; 187.0356; 179.0295; 125.0258 1,3
64 Ferulic acid pentoside 18.03 326.0500 325.0500 193.0474; 178.0238; 134.0347 2
65 Caffeoylshikimic acid 18.03 336.0713 335.0713 179.0325; 173. 0429; 161.0208; 135.0420 2
66 5-O-p-Coumaroylquinic acid 18.50 338.0871 337.0871 191.0514; 173.0417; 163.0356 1,2
67 Unidentified 18.67 578.1268 577.1268 541.1482; 379.0918; 179.0298; 161.0208; 135.0406 4
68 Caffeoylshikimic acid isomer 19.17 336.0713 335.0713 179.0302; 173. 0411; 161.0200; 155.0291; 135.0415 1, 2
69 B-type procyanidin trimer 19.20 866.1873 865.1873 739.1553; 713.1344; 577.1240; 425.0756; 287.0531; 245.0383; 125.0183 3
70 4-O-Feruloylquinic acid 19.75 368.0972 367.0972 191.0531; 173.0423 1,2
71 Caffeoylmalic acid 20.07 296.0416 295.0416 179.0315; 133.115; 115.0010 1,2
72 Procyanidin B (dimer of (epi)catechin) derivative 20.07 880.1656 879.1656 727.1275; 577.1073; 439.0638; 407.0538; 287.0468; 245.0405; 125.0207 3
73 B-type procyanidin trimer 20.38 866.1873 865.1873 739.1553; 713.1344; 577.1292; 451.0938; 425.0813; 407.0716; 287.0522; 245.0383; 125.0207 3
74 (Epi)catechin-(epi)gallocatechin 20.55 594.1023 593.1223 575.1061; 467.1034; 441.0792; 423.0659; 305.0549; 287.0417; 245.0385; 125.0204 3
75 Procyanidin B (dimer of (epi)catechin) derivative 20.76 721.6486 720.6486 644.1217; 577.1295; 289.0645; 245.0399; 125.0202 3
76 Quercetin-O-di-glucoside 21.27 626.1342 625.1342 463.0867; 301.0301; 300.0238; 178.9961; 151.0005 4
77 Quercetin-O-di-rhamnosyl-glucoside/galcactoside 21.28 756.1880 755.1880 609.1432; 300.0275; 271.0254; 178.9947; 151.0029 1,2,3
78 Unidentified 21.74 536.1387 535.1387 491.1498; 323.0715; 281.0600; 179.0314; 161.0215 4
79 Procyanidin dimer monoglycoside 22.18 740.1601 739.1601 587.1146; 459.0606; 449.0773; 435.0625; 289.062; 245.0766; 125.0214 3
80 5,8-Dihydroxy-7-methoxyflavone-O-glucoside-rhamnoside 22.22 592.1811 591.1811; 445.1129 325.0735; 297.0404; 293.0638; 282.0504 1
81 Quercetin-3-O-arabino-glucoside 22.24 596.1230 595.1230 301.0279; 300.0229; 271.0219; 255.0251; 178.9902 4
82 Rutin 23.06 610.1377 609.1377 301.0285; 300.0216; 271.0215; 178.9902; 150.9959 3,4
83 Procyanidin B (dimer of (epi)catechin) 23.25 578.1270 577.1270 451.0997; 425.0849; 407.0722; 289.0671; 125.0228 3
84 Rutin-O-(p-coumaroyl) malate 23.32 890.1862 889.1862 609.1328; 300.0192; 271.0182; 178.9951; 163.0345; 150.9965; 133.0093 1, 2
85 Quercetin derivative hexoside 23.85 566.1131 565.1131 403.1489; 301.0262; 300.0204; 271.0208; 255.0250; 178.9927; 150.9985 4
86 Quercetin-O-glucoside 23.86 464.0778 463.0778 300.0028; 271.0183; 178.9940; 150.9981 1,2,3,4
87 Kaempferol-O-pentoside-hexoside 24.08 580.1286 579.1286 447.0887; 285.0334; 284.0273; 255.0245; 227.0320; 150.9995; 133.0083 4
88 Kaempferol-3-O-rhamnosyl galactoside 24.21 594.1381 593.1381 285.0311; 257.0382; 255.0197; 229.0456; 187.0403 1, 2
89 Ferulic acid 24.26 194.0463 193.0463 178.0225; 149.0556; 134.0330; 117.0299 2
90 Quercetin-O-(glucosyl-feruloylmalate) 24.36 774.1473 773.1473 463.0811; 309.0561; 193.0466; 134.0333 1,2
91 Quercetin-O-pentoside (arabinoside) 24.75 434.0683 433.0686 301.0267; 300.0213; 271.0193; 255.0248; 227.0281; 150.9994 1,2,3
92 Kaempferol-C-di-hexoside-O-hexoside 24.85 772.1694 771.1694 609.1382; 485.1224; 429.0806; 383.0925; 323.0716; 285.0338; 255.0239; 227.0213; 161.0214; 133.0241 4
93 Luteolin-O-glucuronide 25.13 462.0664 461.0664 285.0343; 175.0245; 133.0246; 4
94 Kaempferol-O-glucoside 25.18 448.0832 447.0832 284.0261; 255.0237; 227.0277; 150.9974 1
95 Quercetin-O-(caffeoyl-di-glucoside) 25.44 788.1650 787.1650 625.1372; 461.0677; 387.1494; 301.0286; 300.0232; 179.0375; 161.0161 4
96 Quercetin-O-glucuronide 25.71 478.0832 477.0832 301.0285; 271.0556; 178.9914; 150.9982 1,2,3
97 Quercetin-O-arabinoside-di-glucoside 25.92 758.1530 757.1530 595.1207; 463.0830; 301.0292; 300.0215; 178.9928; 150.9968 4
98 Quercetin-O-glucoside-arabinoside-glucuronide 26.21 772.1694 771.1694 595.1243; 301.0275; 300.0228; 271.0201; 178.9963; 150.9999 4
99 Kaempferol-O-di-pentoside 26.40 550.1142 549.1142 417.0841; 285.0453 1,3
100 Kaempferol-O-pentoside 26.42 418.0743 417.0743 284.0376; 285.0421 1,2
101 Di-caffeoyl-dihydroxybenzoic acid 26.60 478.0983 477.0983 433.1033; 315.0667; 179.0321; 161.0204; 153.0140; 152.0098; 135.0443; 109.0295; 108.0158 4
102 (Epi)-afzelechin-7-O-glucoside 26.82 436.1199 435.1199 345.0936; 273.0730; 167.0336 1
103 Kaempferol-O-(caffeoyl-arabinoside-glucoside 27.09 742.1608 741.1608 579.1326; 455.1050; 429.0733; 285.0349; 284.0270; 255.0312; 227.0223; 179.0308; 161.0221; 135.0376 4
104 Kaempferol-O-rhamnoside 27.88 432.0906 431.0906 285.0431; 284.0317; 255.0287; 227.0334 1,2
105 Quercetin-O-glucoside-arabinoside-glucuronide 27.99 772.1694 771.1694 595.1228; 301.0258; 300.0216; 271.0204; 255.0185; 178.9945; 150.9824 4
106 Kaempferol-O-arabinosisde-glucoside-rhamnoside 29.28 726.1658 725.1658 579.1227; 285.0346; 284.0272; 255.0222; 227.0298 4
107 Luteolin 31.09 286.0364 285.0364 175.0368; 133.0300 4
108 Trihydroxy-octadecadienoic acid 32.36 328.2116 327.2116 291.1989; 229.1460; 211.1336; 171.1031 2,4
109 Unidentified 32.36 396.1960 395.1960 349.2045; 327.2269; 251.1307; 233.1170; 193.0888; 171.1032 1, 3
110 Trihydroxy-octadecenoic acid 33.91 330.2292 329.2292 311.2203; 293.1239; 229.1450; 211.1334; 171.1011 4
111 12-oxo-10E-dodecenoic acid 34.01 228.1222 227.1222 209.1179; 183.1395; 165.1298 1,2
112 Apigenin 34.28 270.0417 269.0417 227.0349; 151.0027; 117.0349; 107.0126 4
113 Trihydroxy-octadecenoic acid derivative 35.261 444.1493 443.1493 329.2280; 309.1244; 293.1891 4
114 12-oxo-10E-dodecenoic acid derivative 43.89 722.3519 721.3519 675.3594; 397.1348; 227.2159 1,4
115 Hydroxy octadecatrienoic acid 47.40 294.2048 293.2048 275.2015; 224.1403; 195.1388 1,2,4
116 Palmitic acid derivative 47.50 700.3671 699.3671 653.7889; 397.1369; 255.2329 1
117 Palmitic acid derivative 48.36 541.3192 540.3192 480.3059; 255.2310 1,3,4
118 Hydroxy octadecadienoic acid derivative 49.62 366.2055 365.2055 317.2080; 295.2254; 277.2110 1,2
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1 Ficus sur leaves-MeOH; 2 Ficus sur leaves-infusion; 3 Ficus sur stem bark-MeOH; 4 Ficus sur stem bark -infusion. The identification was supported by the following sources [24,25,26,27,28,29,30,31,32,33,34,35,36,37].

Figure 1.

Figure 1

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Base peak chromatograms of studied extracts. 1 Ficus sur leaves-MeOH; 2 Ficus sur leaves-infusion; 3 Ficus sur stem bark -MeOH; 4 Ficus sur stem bark -infusion.

2.2. Antioxidant Effects

The role of oxidative stress in the initiation and progression of human diseases supports the systemic antioxidant assessment of plant extracts under investigation. Antioxidants can perform various functions, including hydrogen atom transfer, single electron transfer, and transition metal chelation [38]. In this study, a battery of antioxidant assays was used to obtain a comprehensive understanding of the antioxidant activities of the prepared extracts of F. sur. The assays were: 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric ion reducing antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC), metal-chelating and total antioxidant capacity (phosphomolybdenum). As previously discussed, each test has its own set of advantages and disadvantages [38]. The results are given in Table 3.

Table 3.

Antioxidant properties of Ficus sur extracts.

Parts Solvents DPPH (mg TE/g) ABTS (mg TE/g) CUPRAC (mg TE/g) FRAP (mg TE/g) PBD (mmol TE/g) MCA (mg EDTAE/g)
Leaves MeOH 48.66 ± 0.04 c 81.41 ± 0.05 b 160.80 ± 1.55 c 108.50 ± 2.04 c 1.65 ± 0.11 b 7.88 ± 0.99 c
Infusion 44.22 ± 0.06 c 72.32 ± 1.69 b 147.58 ± 1.59 c 77.28 ± 0.25 d 1.65 ± 0.08 b 22.95 ± 0.20 a
Stem barks MeOH 475.79 ± 6.83 a 804.31 ± 4.52 a 937.86 ± 14.44 a 523.17 ± 2.92 b 5.00 ± 0.30 a 4.62 ± 0.64 d
Infusion 463.58 ± 1.17 b 804.91 ± 5.45 a 910.68 ± 12.14 b 614.33 ± 2.79 a 5.05 ± 0.05 a 13.22 ± 0.18 b
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Values are reported as mean ± SD of three parallel measurements. TE: Trolox equivalents; EDTAE: EDTA equivalents. Different letters in the same column indicate significant differences in the tested extracts (p < 0.05).

Overall, irrespective of the type of extraction solvents used, stem bark extracts demonstrated substantially higher antioxidant activities with DPPH, ABTS, CUPRAC, FRAP, and phosphomolybdenum. For instance, methanolic stem bark extract exhibited the highest DPPH radical scavenging activities (475.79 ± 6.83 mg TE/g). The ABTS assay showed that both methanolic (804.31 ± 4.52mg TE/g) and aqueous stem bark (804.91 ± 5.45 mg TE/g) extracts demonstrated remarkably high activities. ABTS can function with lipophilic and hydrophilic molecules, but DPPH can only be solubilized in organic environments [39]. Our findings confirm the findings of Kim et al. [39]. For example, the DPPH test identified the methanolic extract as the most active, while ABTS identified both methanolic and aqueous extracts as effective ABTS scavengers.

The antioxidant capacity of the extracts was further evaluated in terms of power reduction using the CUPRAC and FRAP tests. Several variables influence antioxidants’ reducing potential, including their ionization potentials, the spin distribution of radical cations, and the bond dissociation energy of the phenolic O-H bond [40]. From Table 3, it can be seen that the methanolic stem bark extract possessed the most potent Cu2+ reducing potential (937.86 ± 14.44 mg TE/g) while the aqueous stem bark extract (614.33 ± 2.79 mg TE/g) was the most robust Fe3+ reducer.

Secondary metabolites are known to have powerful antioxidant properties due to their ability to provide electrons and because they chelate transition metals [41]. Data shown in Table 3 show that the aqueous leaves extract exhibited the highest chelating abilities (22.95 ± 0.20 mg EDTAE/g) while the methanolic stem bark extract displayed the lowest activity (4.62 ± 0.64 mg EDTAE/g). The prepared samples were also tested for their total antioxidant capacity (phosphomolybdenum assay). The latter test is based on antioxidants reducing Mo (VI) to Mo (V), resulting in the formation of a green complex in acidic conditions [42]. The aqueous stem bark extract showed the highest capacity (5.05 ± 0.05 mmol TE/g). It is noteworthy that the stem bark extracts showed stronger antioxidant ability than the leaf extracts for all assays, except the metal-chelating assay. Consequently, it can be said that the antioxidant activity of the active samples could be associated with the presence of bioactive compounds.

2.3. Enzymatic Inhibitory Activities

In the present study, the ability of F. sur extracts to modulate the activity of enzymes related to Alzheimer’s disease [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)], diabetes type 2 (α-amylase and α-glucosidase), and skin hyperpigmentation (tyrosinase) was investigated. The results are presented in Table 4.

Table 4.

Enzyme inhibitory properties of Ficus sur extracts.

Parts Solvents AChE (mg GALAE/g) BChE (mg GALAE/g) Tyrosinase (mg KAE/g) Amylase (mmol ACAE/g) Glucosidase (mmol ACAE/g)
Leaves MeOH 2.11 ± 0.24 b 2.31 ± 0.21 b 68.12 ± 0.47 b 0.61 ± 0.01 c 3.98 ± 0.03 a
Infusion na na 0.35 ± 0.08 d 0.13 ± 0.01 d 3.90 ± 0.01 b
Stem barks MeOH 2.91 ± 0.07 a 6.56 ± 0.34 a 69.84 ± 0.35 a 0.77 ± 0.01 a na
Infusion 1.88 ± 0.11 b na 51.55 ± 0.24 c 0.74 ± 0.02 b na
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Values are reported as mean ± SD of three parallel measurements. GALAE: Galantamine equivalents; KAE: Kojic acid equivalents; ACAE: Acarbose equivalents; na: not active: Different letters in the same column indicate significant differences in the tested extracts (p < 0.05).

Because enzymes in the human body contribute to the genesis of disease, inhibiting these enzymes can be advantageous in health care. Cholinesterase inhibitors, for example, are drugs that prevent the breakdown of acetylcholine, a neurotransmitter in the central nervous system that, when present in excessive concentrations, can cause neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease [43]. Our study explored the anti-cholinesterase activity in various extracts of F. sur. High anti-AChE and anti-BChE activities were recorded with the methanolic stem bark extract (2.91 ± 0.07 and 6.56 ± 0.34 mg GALAE/g, respectively). However, the aqueous leaves extract was inactive against AChE and BChE.

Inhibitors of α-amylase and α-glucosidase diminish carbohydrate digestion in the small intestine and, as a result, lower postprandial blood glucose levels, making them an essential therapy option for type II diabetes patients [44]. The methanolic stem bark extract of F. sur was observed to substantially depress α-amylase (0.77 ± 0.01 mmol ACAE/g) but was found to be inactive against α-glucosidase. Instead, the methanolic leaves extract showed high anti-glucosidase activity (3.98 ± 0.03 mmol ACAE/g).

Tyrosinase inhibitors help to protect the skin and prevent hyperpigmentation. They are strongly promoted by the pharmaceutical and cosmetics industries [45]. The methanolic stem bark extract displayed the strongest anti-tyrosinase activity (69.84 ± 0.35 mg KAE/g), while the aqueous leaves extract showed the lowest activity (0.35 ± 0.08 mg KAE/g). It is noteworthy that the methanolic stem bark extract showed the highest activity against four enzymes, namely AChE, BChE, tyrosinase, and α-amylase, although, the extract did not show the highest TFC and TPC.

2.4. Cytotoxicity Evaluation

Cytotoxicity evaluation revealed that the infusion and methanolic extract from Ficus sur leaves exerted low toxicity on normal kidney fibroblasts (VERO); the exact CC50 values could not be evaluated because they were above the tested concentration range (Table 5). Stem bark extracts showed a similar effect on VERO cells. Selective toxicity towards HeLa cancer cells was observed for Ficus sur leaves methanolic extract (FLM) and infusion (FLI) with SI of >3.62 and >2.36. In contrast, in the case of RKO, only FLM showed selective toxicity (SI > 3.13). Significant antineoplastic activity towards both cancer cell lines was observed (Figure 2) for Ficus sur stem bark methanolic extract (FSBM) and infusion (FSBI) with CC50 values ranging from 36.8 to 56.12 µg/mL. The anticancer selectivity of FSBM and FSBI towards HeLa cells was 7.1 and 9.24, respectively, whereas against RKO, it was found to be 5.37 and 7.01, respectively. Multiple studies describe the anticancer potential of Ficus spp, ex. Ficus carica [46,47], Ficus salicifolia [46], Ficus religiosa [48], Ficus beecheyana [49], Ficus pandurata H [50] and Ficus exasperata (Vahl) [51], against various cancer cell lines, however, to the best of our knowledge, this is the first report showing Ficus sur stem bark extracts as a possible source of antineoplastic molecules.

Table 5.

Results of cytotoxicity evaluation.

Ficus sur Solvent CC50 ± SD (µg/mL)
VERO HeLa RKO
Leaves MeOH FLM >500 138.3 ± 3.78 159.97 ± 12.3
Infusion FLI >500 212.0 ± 19.45 594.23 ± 41.0
Stem bark MeOH FSBM 340.1 ± 22.72 47.89 ± 0.27 36.8 ± 4.92
Infusion FSBI 301.12 ± 30.31 56.12 ± 1.89 42.96 ± 4.94
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Figure 2.

Figure 2

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Influence of Ficus sur extracts on normal and cancer cells.

2.5. Antiviral Potential

The Ficus sur extracts were incubated with an HHV-1 infected VERO cell line to evaluate the antiviral potential. After CPE was found in the virus control cells, the influence on CPE was observed in extract-treated infected cells. It was found that only one extract, namely FLM at 250 µg/mL, decreased, but did not abolish altogether, CPE formation, as can be seen in Figure 3. The collected samples were further subjected to an end-point dilution assay to evaluate the infectious titer of HHV-1. The data on HHV-1 titer reduction contained in Table 6 confirmed that FLM 250 µg/mL exerted antiviral activity, decreasing the infectious titer by 2.86 log. However, since it is generally agreed that the tested sample should reduce the infectious titer by at least 3 log to show significant antiviral potential, FLM cannot be regarded as such. However, plant extracts are complex mixtures of compounds belonging to various groups of secondary metabolites, and the biological activity of such extracts depends on their composition, and the relative amount of particular substances and possible biological interactions (ex. synergism or antagonism). One of the end-point dilution assays performed for virus-infected cells treated is presented in Figure 4; in this particular experiment, the reduction of HHV-1 titer was 3.1 log. Considering this, the reported results can be regarded as interesting, and the observed antiviral activity will be further evaluated to elucidate the compounds responsible.

Figure 3.

Figure 3

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Influence of Ficus sur leaves methanolic extract on HHV-1 generated cytopathic effect.

Table 6.

Abatement of HHV-1 infectious titer in response to Ficus sur treatment.

Ficus sur Solvent Concentration
(µg/mL)		 Decrease of HHV-1 Infectious Titer (Δlog *)
Leaves MeOH 250 2.86 ± 0.17
125 1.03 ± 0.23
Infusion 100 0.52 ± 0.19
50 0.09 ± 0.16
Stem bark MeOH 125 0.12 ± 0.06
62.5 0.07 ± 0.25
Infusion 125 0.92 ± 0.52
62.5 0.35 ± 0.13
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* Δlog (mean ± SD)–calculated from separate titration assays; Δlog = logCCID50VC–logCCID50E; VC–virus control; E–extract, Δlog ≥ 3 is regarded as significant.

Figure 4.

Figure 4

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Titration assay of HHV-1 in the sample treated with Ficus sur leaves methanolic extract.

We have previously reported that Oenanthe aquatica and Oenanthe silaifolia extracts possess significant antiviral activity, and the observed effect may be related to the presence of caffeic acid and its derivatives (caffeic acid glucoside, chlorogenic acid, cryptochlorogenic acid, and neochlorogenic acid) present in those extracts [52]. Interestingly, caffeic acid derivatives were identified in the FLM, which showed the highest anti-HHV-1 activity, and in FSBI, which exerted a noticeable, though much lower, influence on the tested herpes virus, reducing the infectious titer only by 0.92 log. Furthermore, methyl gallate, detected exclusively in the FLM, was proven to be a potent and specific inhibitor of HHV-2 [53]. Additionally, FLM was the only extract showing the presence of 5,8-dihydroxy-7-methoxyflavone-O-glucoside-rhamnoside; there are reports of antiviral activity of some flavone compounds ex. 5,7-dihydroxy-3,4′-dimethoxyflavone (ermanin) and 5,7,4′-trihydroxy-3-methoxyflavone (isokaempferide) against polio [54] or 5,7,4′-trihydroxy-8-methoxyflavone against influenza virus [55], while 5-hydroxy-7-methoxyflavone and 5,7-dimethoxyflavone were found to be protease inhibitors active against HIV-1, HCV, and HCMV (Human cytomegalovirus, HHV-5, CMV) at micromolar concentrations [56]. The kaempferol-O-glucoside present in FLM was also isolated from Securigera securidaca and reported to inhibit HHV-1 attachment to the cell membrane, virus entry and viral polymerase [57], and showed potent anti-HIV-1 reverse transcriptase activity [58]. Flavone glycosides, namely quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside and kaempferol-3-O-robinobioside, were reported by Yarmolinsky et al. [59] as being responsible for the antiviral potential of Ficus benjamina. Interestingly, isolated glycosides exerted significant antiviral activity against HHV-1 and HHV-2, especially when added to infected cells during and after infection, but no activity was found against HHV-3 (varicella-zoster virus, VZV). Flavone aglycones, kaempferol and quercetin, obtained as standards, showed significantly lower activity [59]. Finally, FLM was the only extract that showed the presence of (epi)-afzelechin-7-O-glucoside, and of note, ent-epi-afzelechin-(4-8)-epiafzelechin was reported to inhibit HHV-2 by disrupting virus penetration and interfering with late stages of the viral replication cycle [60].

3. Materials and Methods

3.1. Plant Materials and Preparation of Extracts

Ficus sur samples were collected in the village of Prikro (city of Brobo, Côte d’Ivoire), in January 2020. The species was identified by a plant taxonomist at the National Floristic Center (Universite Felix Houphouet Boigny, Abidjan, Côte d’Ivoire). Voucher specimens were deposited at the herbarium of the above-mentioned center. The leaves and stem barks of the plant samples were dried in shade conditions at room temperature for about one week. Then, the samples were powdered with a mill and stored in dark conditions.

Different solvents (methanol and water) were used to obtain the extracts in this study. Maceration was used as the extraction method for methanol extracts. In addition, the infusion was prepared. For the maceration, the plant materials (10 g) were macerated with 200 mL methanol at room temperature overnight. After that, the mixtures were filtered, and the solvents were evaporated. In preparing the water extracts, the plant materials (10 g) were kept with 200 mL boiled water for 15 min and then filtered. Water extracts were lyophilized, and all extracts were stored at 4 °C until analysis.

3.2. Chromatographic Conditions

The separation was performed on a C18 Gemini® column (3 µm i.d. with TMS end-capping, 110 Å, 100 × 2 mm) supported with a guard column (Phenomenex Inc, Torrance, CA, USA), at a flow rate of 0.2 mL/min under a gradient program operated by Agilent 1200 Infinity HPLC (Agilent Technologies, Santa Clara, CA, USA). Solvent A was water with 0.1% formic acid (v/v), whereas solvent B was 0.1% formic acid in acetonitrile (v/v). Both solvents were mixed according to the following program: 0–60% B for 45 min., next 60–95% B for 1 min., and 95% B for 4 min. The stop time was at 50 min. 10 μL of the sample was injected into a thermostated (20 °C) chromatographic column.

3.3. Detection Conditions

Mass spectra were acquired by the Agilent 6530B QTOF Accurate-Mass QTOF system equipped with Dual Agilent Jet Stream spray source (ESI) (Agilent Technologies, Santa Clara, CA, USA) connected with N2 generator (Parker Hannifin Corporation, Haverhill, MA; generating N2 at purities >99%). Negative ion mode was applied for MS and MS/MS acquisition with drying gas temp: 275 °C, drying gas flow: 10 L/min, sheath gas temp: 325 °C, sheath gas flow: 12 L/min; nebulizer pressure: 35 psig, capillary V (+): 4000 V, skimmer 65 V, fragmentor 140 V. Two spectra per sec were recorded in a range between 100 and 1000 m/z with a collision energy of 10 and 40 eV. The identification of compounds was based on fragmentation patterns and supported by a comparison of obtained mass spectra with those available in databases and the scientific literature.

3.4. Total Phenolic and Flavonoid Content

Total levels of phenolics and flavonoids were assessed based on previously reported methods [61,62]. Total phenolic levels were expressed as mg gallic acid equivalents (GAE)/g dry extract, and mg rutin equivalents (RE)/g dry extract was used to evaluate total flavonoids. All experimental details are given in the Supplementary Materials. The experiments were performed in triplicate, and the results were assessed by ANOVA assays (Tukey’s test).

3.5. Antioxidant and Enzyme Inhibitory Assays

In the current investigation, the antioxidant effects of the tested extracts were detected by different assays [61]. The assays were: [1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline) 6-sulfonic acid (ABTS) radical scavenging, cupric ion reducing antioxidant capacity (CUPRAC), ferric ion reducing antioxidant power (FRAP), metal chelating ability (MCA) and phosphomolybdenum assay (PDA)]. For DPPH, ABTS, CUPRAC and FRAP assays, data were expressed as mg Trolox equivalents (TE)/g extract, whereas in MCA and PDA, mg EDTA equivalents (EDTAE)/g extract and mmol TE/g extract, respectively, were used. The experimental details for acetylcholinesterase, butyrylcholinesterase, tyrosinase, amylase and glucosidase assays were previously provided. Galanthamine was used as a positive control in cholinesterase assays, and data were evaluated as mg galanthamine equivalents (GALAE)/g extract. Kojic acid was used as a standard inhibitor in tyrosinase inhibitory assay, and the results were expressed as mg kojic acid equivalents (KAE)/g extract [61,62]. Acarbose was selected as an inhibitor of both amylase and glucosidase in the antidiabetic assays, and the results are given as mmol acarbose equivalents (ACAE)/g extract. All experimental details are given in the Supplementary Materials. The assays were performed in triplicates, and the differences in the extracts were evaluated by ANOVA (Tukey’s test).

3.6. Cytotoxicity Testing

The evaluation of cytotoxicity was performed against normal kidney fibroblasts (VERO) and cancer cell lines derived from cervical adenocarcinoma (HeLa) and colon cancer (RKO) using microculture tetrazolium assay (MTT) as previously described [52]. Briefly, the cell monolayers were incubated with serial dilutions of the tested extracts for 72 h, and then cellular viability was assessed using the MTT protocol. Details can be found in the Supplementary Materials. The collected data were analyzed using GraphPad Prism to calculate the CC50 values (50% cytotoxic concentration). Additionally, selectivity indexes (SI) were calculated by comparing CC50 values obtained for VERO with those observed for cancer cells (SI = CC50VERO/CC50Cancer, SI > 1 indicates selectivity towards cancer cells).

3.7. Evaluation of Antiviral Potential

The extracts in non-toxic concentrations were tested for their influence on HHV-1 replication in the virus-infected VERO cells after 72 h incubation as previously described [52]. Briefly, the monolayer of VERO cells was treated with HHV-1 (100-fold CCID50, CCID50–50% cell culture infections dose) for 1 h, followed by washing with PBS (phosphate-buffered saline) and further incubated until a cytopathic effect (CPE) was recorded in the virus control (VC). Subsequently, after three cycles of freezing (−72 °C) and thawing, the HHV-1 infectious titer in the collected samples was measured using an end-point titration assay. Finally, the HHV-1 titer (Δlog) difference was calculated (Δlog = logCCID50VC–logCCID50FE, FE-Ficus extract). The difference of ≥3 log is regarded as significant.

4. Conclusions

In conclusion, the F. sur methanolic stem bark extract demonstrated substantial in vitro antioxidant potential with DPPH, ABTS, and CUPRAC assays, but not with FRAP, metal-chelating and phosphomolybdenum assays. The methanolic stem bark extract significantly depressed tyrosinase, α-amylase, AChE and BChE activity. To date, no evidence of enzyme inhibitory actions of Ficus members has been discovered. In this regard, the presented work is the first scientific demonstration of the enzyme inhibitory effects of F. sur extracts, and it may offer a substantial contribution to the scientific platform. Herein, we would like to report that the F. sur leaves methanolic extract exerted noticeable, but limited, antiviral activity against HHV-1, diminishing CPE development and reducing the virus titer by 2.86 log. Furthermore, antineoplastic activity against cervical adenocarcinoma and colon cancer cell lines was observed for stem bark infusion and methanolic extract. However, more study, including in vivo and clinical investigations, is needed to further examine these aforementioned properties to incorporate this traditional herb as a possible therapeutic element.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27061863/s1.

Click here for additional data file. (275.1KB, zip)

Author Contributions

Conceptualization, E.S., Ł.Ś. and G.Z.; methodology, E.S., Ł.Ś., K.I.S., G.Z., A.B., M.P.-D. and O.K.E.; software, E.S. and Ł.Ś.; validation, K.I.S. and G.Z.; formal analysis, G.Z.; investigation, E.S., K.I.S., G.Z., N.B.S. and M.F.M.; resources, G.Z. and O.K.E.; data curation, E.S., Ł.Ś. and G.Z.; writing—original draft preparation, E.S., Ł.Ś., N.B.S. and M.F.M.; writing—review and editing, G.Z.; visualization, Ł.Ś.; supervision, E.S.; project administration, G.Z.; funding acquisition, E.S. and Ł.Ś. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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