Herbal anthelmintic agents: a narrative review

Abstract

Helminths or Parasitic worms of humans may cause chronic and sometimes deadly diseases, considered as neglected tropical diseases (NTDs) that infect around two billion people worldwide. Plants have been used as anthelmintics from ancient times. This review is a compilation of plants as source of anthelmintic drug. All information presented in this review article regarding the anthelmintic activities of plants from 2005 and has been acquired by approaching various electronic databases, including Scopus, Google scholar, Web of science and PubMed. Literature was surveyed for anthelmintic activity of plants which showed that secondary metabolites of plants like terpenes, glycosides, saponins, flavonoids, tannins and alkaloids were having anthelmintic activity. Since this review is a compilation of anthelmintic activity of plants from the year 2005, it will definitely be a fruitful study for researchers working in this field.

1. INTRODUCTION

Parasitic worms or helminths cause chronic and sometimes deadly diseases that have a major socio-economic impact worldwide.¹ In humans, the disease caused by the parasitic worms is about 14 million globally, also called neglected tropical diseases (NTD).²In agricultural animals, diseases caused by parasites led to losses of about billions of dollars per year throughout the world.^3,4

Gastrointestinal nematodes (GI), such as hookworms, whipworms, and roundworms affected under 15 years most.⁵Approximately more than 10% of the population is infected by GI nematodes worldwide.⁶

As of now, no vaccines are available in the market, so, control of helminths lies on the some of effective drugs, called anthelmintics, but their inadequate use causes serious drug resistance problems worldwide, so, urgent need is there for isolating, identifying new anthelmintic drugs,⁷ for humans, its lies on chemotherapy.⁸ Parasitic nematodes in human are two types : intestinal nematodes and tissue or blood nematodes.⁹ Intestinal nematodes includes -Ancylostoma duodenale, Trichuris trichiura, Ascaris lumbricoides, Enterobius vermicularis, and Strongyloides stercoralis, etc.¹⁰

Helminths lives in the GI tract of their hosts, and feed off living hosts, taking nutrients from host and causing infection/diseases and normally more prone to children, soil-transmitted schistosomiasis and helminthiasis are the most significant helminthiases, responsible for neglected tropical disesses.^11,12 It also causes indirect disease burden through the immune system impairment, leads to malaria, tuberculosis, or human immunodeficiency virus/acquired immunodeficiency syndrome.¹³

Adult parasites survive for a long time in their human host and feeds directly from the blood of their hosts, thus helminths cause iron-deficiency anemia.¹⁴ Chronic helminth infections are characterized by a Type II helper T cells type response.^{15,⇓,⇓,⇓-19}

2. HELMINTHS AND ANTHELMINTICS

Helminths cause a number of diseases in humans and animals, which are summarized in Table 1.

Table 1.

Diseases caused by helminths

Type of Helminths	Species	Diseases
Cestodes (Tapeworm)	Coenurus cerebralis - In sheep, rabbits, and rodents, - Humans become an intermediate host after ingesting food contaminated.	Coenurosis - Involvement of CNS. -Cysts are developed into ventricles, and sometimes within the parenchyma of the brain, spinal cord.20
	Diphyllobothrium latum - The fish tapeworm, infect humans who ingest raw and pickled freshwater fish. - Compete with hosts for certain vitamins and related substances particularly for vitamin B12 and split vitamin B12 intrinsic factor complex.	Diphyllobothriasis - Low concentration of vitamin B12 - Systemic and neurologic symptoms, including pallor, glossitis, loss of tongue papillae, numbness, paresthesias of feet and hand, depression, loss of vibratory sensation. - Optic neuropathy.21,22
	Spirometra species - Cats and dogs (definitive host). - Humans are accidental hosts, acquire infection by drinking contaminated water. - Penetrate intestinal wall and migrate to brain and other tissues and grow to full size.	Sparganosis - Slow-growing, tender, migratory, subcutaneous nodules develop for several weeks or years. - Symptoms like fever, chill, edema, and peripheral eosinophilia. - In rare case, helminths travel to the eye and brain.2
	Taenia solium - Tapeworms, migrate through the mucosa and enter in the CNS, eyes, and striated muscle.	Cysticercosis - Affects CNS, causes fever, headaches during the larval stage, progressive muscle weakness.26
Nematodes	Angiostrongylus cantonensis - Infect mollusks or fish. - In humans, it affects the upper respiratory tract, CNS	Angiostrongyliasis - Characterized by eosinophilic meningitis - Symptoms are rash, pruritus, abdominal pain, headache, stiff neck, vomiting, etc.28
	Gnathostoma spinigerum - Parasitizes the stomachs of cats and dogs. - Migrate through human tissue by ingestion of cooked animal flesh, drinking contaminated water	Gnathostomiasis - Mainly CNS can be affected, the spinal cord is affected initially. - Patients experience nausea, vomiting, upper abdominal pain, urticaria, pruritus, etc.27
	Loa loa - Group of nematodes, also called filaria. - White, threadlike worms transmitted to humans by biting tabanid flies.	Loiasis - Infections are usually asymptomatic. - To treat loasis, one should consult an expert on tropical infectious diseases.29
	Onchocerca volvulus - Similar to Loa loa. - Transmitted to humans by female black flies.	Onchocerciasis - Granulomatous reaction followed by fibrosis. - Skin lesions, characterized by erythematous, pruritis, rash, etc.29
	Strongyloides stercoralis - Small nematodes, can parasitize the small bowel of humans. - This female worm hatch in the intestinal duodenum and jejunum and pass into feces.	Strongyloidiasis - Infection is caused in humans by skin contact with the contaminated soil. - Intestinal parasitism30
	Toxocara canis and cati - Infects dogs and related mammals. - Eggs hatch into the small intestine of the host and larvae migrate into lungs, and trachea.	Toxocariasis - Human toxocariasis occurs accidentally by ingesting the faeces of infected dogs. - Conditions may develop to the eye, CNS, producing nonspecific systemic manifestations.31
	Trichinella spiralis - Human infection occurs by eating raw and undercooked pork, bear, wild boar. - After eating, the larvae migrate to the stomach, then to the small intestine.	Trichinosis - Characterized by abdominal pain, vomiting, and diarrhea followed by fever, headache, lethargy, and severe muscle pain, weakness and tenderness.32
	Paragonimus spices - Lung flukes, humans and other mammals are the final host, first intermediate host are snails, second intermediate host crustaceans. - Penetrating intestinal wall, entering into peritoneal cavity then migrating through diaphragm go to lungs. Schistosoma spices - Humans and other mammals are the final host, first intermediate host are snails, second intermediate host are crustaceans. - Found in intramedullary granuloma, spinal cord, CNS	Paragonimiasis - Most cases mild and asymptomatic. - Brownish sputum with cough and intermittent hemoptysis. - Chronic bronchitis.27 Schistosomiasis - Involvement of CNS. - Chronic schistosomiasis is more common than acute. - Acute schistosomiasis is caused by an immunological response to helminths. Chronic schistosomiasis is an inflammatory response to eggs.27

Notes: CNS: central nervous system.

2.1. Anthelmintics

Anthelmintics, the term used for a group of drugs, used to treat several infections of humans and animals, mainly caused by parasitic worms.³³

2.1.1 Secondary metabolites of plants having anthelmintic activity

Allelochemicals of plants are produced from all plants,³⁴primary metabolites acts as precursors of different secondary metabolites.³⁵ Secondary metabolites includeing Alkaloids, Terpenes, Flavonoids, Resins and Phenolic compounds are responsible for colour, flavour, fragrance of different plant.³⁶ Terpinen-4-ol was having LC₅₀ = 4.1 mM and LC₉₀ = 20.2 mM.

Secondary metabolites having anthelmintic activity are summarized in Figure 1.

Figure 1. Secondary metabolites having anthelmintic activity.

C_50: lethal concentration 50.

Terpenes: terpenes are the combination of different isoprene units (C₅H₈).³⁶ Its shows anthelmintic activities causing intestinal damage to the parasite.³⁷ Examples are terpinen-4-ol, borneol, and β-elemene showed activity against H. contortus by inhibiting egg hatching.³⁸ Ter-penes having anthelmintic activity are given in Figure 2.

Figure 2. Terpenes having anthelmintic activity.

ED50: median effective dose; EC50: half maximal effective concentration.

Glycosides: glycosides, have potent activity against different helminths.^39,40 Cardenolide causes disturbance of sodium and potassium ions transportation into helminths, thus, causing death of helminths.⁴¹ Glycosides having anthelmintic activity are given in Figure 3.

Figure 3. Glycosides having anthelmintic activity (LC50 = 80.4 µM).

LC50: lethal concentration 50.

Saponins: saponins contains triterpene or sometimes steroidal-aglycone with sugar chains.⁴² Saponins show their anthelmintic activity by inhibiting acety-lcho-linesterase and thus cause worm paralysis leading to death.⁴³ They are reported to have inhibitory activity against animal parasitic nematodes, like-Haemonchus contortus.⁴⁴ β-Sitosterol was having IC₅₀ value 58 µM. Saponins having anthelmintic activity are given in Figure 4.

Figure 4. Saponins having anthelmintic activity.

Flavonoids: flavonoids, helps in UV protection, flower coloring, allelopathy, and auxin transport inhibition.⁴⁵ Flavonoidal plant, showing activity by blocking the phosphorylation reaction, thus inhibit the energy production within the parasitic worms, leading to death.⁴⁶ Quercetin was having paralysis time at 10 mg/mL = 2.23 ± 4.51 min. Flavonoids having anthelmintic activity are given in Figure 5.

Figure 5. Flavonoids having anthelmintic activity.

Tannins: tannins, water-soluble, polyphenolic group of compounds, help in the killing of nematodes, by interfering with nutrients absorption of worms from the host cell⁴⁶ or when the condensed tannins are ingested by larvae, the tannin binds to the intestinal mucosa of the parasitic worms and thus causes autolysis.⁴⁷ Epigallocatechin was having IC₅₀ value 49 µM. Tannins having anthelmintic activity are given in Figure 6.

Figure 6. Tannins having anthelmintic activity.

Alkaloids: alkaloids have shown anthelmintic activity by targeting acetylcholine receptor and suppressing glucose uptake, thus helminths died due to starvation.⁴⁸Dicentrine was having EC₉₀ = 6.3 µg/mL and san-guinarine was having IC₅₀ = 58 µM. Alkaloids having anthelmintic activity are given in Figure 7.

Figure 7. Alkaloids having anthelmintic activity.

Non-protein amino acids: non-protein amino acid are the nitrogen-containing compounds having ammonia derivatives compounds with hydrogen atoms. They damage the parasitic worms by affecting the CNS of parasitic worms, leading to paralysis and followed to death.⁴⁹ Mimosine was having IC₅₀ = 16.8 µM Non-protein amino acids having anthelmintic activity are given in Figure 8. Target Sites of anthelmintics Target sites for anthelmintic are summarized in Tables 2 and 3.

Figure 8. Non-protein amino acids having anthelmintic activity.

Table 2.

Ion-channels as target sites for anthelmintics

Parasite group	Target site	Example
Nematodes	Nicotinic acetylcholine receptor agonists	Levamisole
Large intestinal nematodes	Gamma-Aminobutyric acid receptor agonists	Piperazine
Nematodes and insect parasites	Glutamate-gated chloride channel receptor potentiators	Ivermectin
Cestodes and trematodes	Membrane calcium permeability enhancers	Praziquantel

Table 3.

Target sites for anthelmintics (other than ion-channels)

Parasite group	Target site	Example
Nematodes, cestodes and trematodes	β-tubulin binders	Thiabendazole
Blood feeders: flukes, Haemonchus contortus, Oestrus ovis	Proton ionophores	Closantel
Immature Fasciola	Malate metabolism inhibitors	Diamphenethide
Fasciola	Phosphoglycerate kinase and mutase inhibitors	Clorsulon
Filaria	Arachidonic acid metabolism inhibitors	Biethylcarbamazine

2.1.3 Classes of natural products having anthelmintic activity

Different classes of natural products are reported to have anthelmintic activities.

Phenols: phenolic compounds contain a functional heterogenous group attached with its aromatic ring. Groups like-flavonoids, isoflavonoids and tannins are included in the phenolic compounds,⁴⁵ showing activity by changing the phosphatase enzyme in the helminths tegument.⁵⁰

Phenols having anthelmintic activity include:

Monophenols (cresols, thymols, and carvacrol): carvacrol and thymol showed activity against C. elegans and Ascaris suum.⁵¹ Monophenols having anthelmintic activity are given in Figure 9.

Figure 9. Monophenols having anthelmintic activity.

IC50: half maximal inhibitory concentration.

Benzene diols (resorcinols and catechols): gallic acid analogues, catechin-3-O-gallate and four related proanthocyanidins showed activity against C. elegans and O. ochengi.⁵² Benzene diols having anthelmintic activity are given in Figure 10.

Figure 10. Benzene diols having anthelmintic activity.

Substituted benzoic acids (vanillic acids and gallic acids): showed activity against nematode C. elegans and Onchocerca ochengi.⁵³ Substituted benzoic acids having anthelmintic activity are given in Figure 11.

Figure 11. Substituted benzoic acids having anthelmintic activity.

Cinnamic acid: cinnamic acid exhibited action by inhibiting egg hatching, example of some are p-coumaric, caffeic acid, ferulic acid, naringenin, quercetin and luteolin, procyanidins are having anthelmintic activity.⁵³ Cinnamic acid derivatives having anthelmintic activity are given in Figure 12.

Figure 12. Cinnamic acid derivatives having anthelmintic activity.

Prenyl derivatives: farnesyl pyrophosphate and geranyl pyrophosphate, precursors of prenyl groups, linalool, active against Brugia malayi and Dirofilaria immitis.⁵⁴ Prenyl derivatives having anthelmintic activity are given in Figure 13.

Figure 13. Prenyl derivatives having anthelmintic activity.

Macrocyclic Lactones: macrocycles includes macrolide and glyco lipopeptide, having anti-nematocidal activities, avermectins (Figure 14) and their aglycons are produced by soil microorganism Streptomyces species.⁵⁵

Figure 14. Macrocyclic lactone having anthelmintic activity.

Miscellaneous compounds: piperine from Piper nigrum and strychnine from Strychnos nux-vomica showed activity against several helminths. Structures of piperine and strychnine are given in Figure 15.

Figure 15. Piperine and strychinine.

2.1.4 Plants having anthelmintic activity

A number of plants are reported to have anthelmintic activities. Some of them are as follows:

Commiphora molmol: there are a number of reports indicating that over 90% of humans are suffering from schistosomiasis, fascioliasis.⁵⁶Myrrh was effective against Trichinella spiralis at a dose of 0.01 mL per infective mouse (Trichinella spiralis infective mouse), half maximal effective concentration (EC₅₀) value for Commiphora molmol was 0.20 mg/mL.⁵⁷

Ocimum sanctum: Occimum sanctum showed its activity at a dose of 62.15 mg/mL against Caenorhabditis elegans.⁵⁸Crude hydro-alcoholic extract was tested at dose concentration of 20 and 40 mg/mL against Pheritima posthuma. For 20 mg/mL paralysis at (6.0 ± 0.5) min and death at (13.5 ± 1.2) min.⁵⁹

Melia azedarach: hexane extract of M. azedarach fruits, effective against parasites, showed a significant lethal concentration 50 (LC₅₀) value at 572.2 μg/mL and lethal concentration 99 (LC₉₉) value at 1137.8 μg/mL.⁶⁰

Artemisia annua: the plant crude leaves extract was tested against H. contortus, showed lowest LC₉₉ at 1.27 μg/mL in egg hatch test assay, and in the larval development test assay, showed LC₉₉ at 23.8 μg/mL.⁶¹

Carica papaya: the latex of the plant Carica papaya tested against Pheretima posthuma, with different concentrations (20%, 50% and 100%), at 100% concentration, it shows paralysis time, P = 24.5 min and death time, D = 56 min.⁶²

Nigella sativa: ethanolic extract, tested against Cotylophoron cotylophorum at 5% concentration, it showed 81.02 % inhibition of the motility after the exposure of 8 h.⁶³

Flemingia vestita: the isoflavones of the plant Flemingia vestita were tested against Rallietina echinobothrida with paralysis time for glucose 6-phosphate dehydrogenase is 0.880 ± 0.006 and for pyruvate carboxylase is 9.2 ± 0.2 and for fructose 1, 6-bisphosphatase is 0.98 ± 0.15.⁶⁴

Juglans regia: crude acetone extract showed anthelmintic activity at 10 mg/mL, with paralysis time (52.00 ± 0.20) min and death at (114.00 ± 0.14) min. Crude methanolic extract showed its anthelmintic activity at 10 mg/mL, with paralysis time (100.00 ± 0.14) min and death at (133.00 ± 0.18) min when tested against Eicinia feotid.⁶⁵

Mimusops elengi: the methanolic extract was tested against Pheretima posthuma, showing anthelmintic activity at 5 mg/mL, causing paralysis and death of the helminths at 163.3, 223.2 min respectively.⁶⁶

Punica granatum: the crude methanolic tested against Haemonchus contortus, at 10 mg/mL it produced mortality at P < 0.05, hatching inhibition at 0.1 mg/mL upto 49.33% and 46.33%.⁶⁷

Thymus vulgaris: essential oil of Thymus vulgaris was tested against H. contortus, 90% inhibition was observed at concentrations 50 to 0.781 mg/mL, and half maximal inhibitory concentration (IC₅₀) value was 0.436 mg/mL. 97.0% larval motility inhibition observed at concen-trations 50 to 3.125 mg/mL and IC₅₀ value 0.338 mg/mL.⁶⁸

Ferula foetida: aqueous extracts were treated against Pheretima posthuma, exhibited activity at 100 mg/mL in 6 min (caused paralysis of the worms). Aqueous extract of the plant at 25 mg/mL caused helminths paralysis in (24.00 ± 0.14) min and death in (56.00 ± 0.17) min.⁶⁹

Embelia ribes: methanolic extracts was tested against Ascaridia galli, at a dose of 60 mg/mL it showed activity 38.67% ± 4.10% and 38.67% ± 1.86%, after 48 h of incubation.⁷⁰

Vernonia anthelmintica: ethanoic extracts were tested against Haemonchus contortus, survival rate reduced significantly at a dose conc. of 80 μg/mL.⁷¹

Chenopodium ambrosioides: the ethanolic extract was tested against Haemonchus contortus, showed lethal effect (about 96.3%) at 40 mg/mL, after 72 h incubation⁷² and the EC₅₀ value of Chenopodium ambrosioides was (0.26 ± 0.02) mg/mL.⁷³Hydro-alcoholic extract tested against Schistosoma mansoni, larvae died at different doses after 180 min.⁷⁴

Piliostigma thonningii: the ethanolic extract was tested against Ascardia galli, showing anthelmintic activity, about 60% of larval paralysis at a dose conc. of 4.4 mg/mL within 24 h of exposure.⁷⁵

Ginkgo biloba: aqueous extract of plant was tested against S. papillosus, 3.0% of plant extract solution, mortality rate of nematode larvae was 92.3% ± 2.9%, in 0.75% of plant extract solution.⁷⁶ Petroleum-ether extract tested against Pseudodactylogyrus, at 6.0 and 2.5 mg/L, its having median effective dose (ED₅₀) value 2.88 and 0.72 mg/L, respectively.⁷⁷

Asparagus racemosus: rhizome extract at a dose of 5 mg/ ml showed mortality time (2.30 ± 0.29) h. At a dose of 10 mg/mL, plant extract showed mortality time (2.09 ± 0.05) h, etc.⁷⁸

Trifolium repens: aerial shoot extract tested against the tapeworm Hymenolepis diminuta with different compounds i.e. 1 mg/mL betulinic acid, 0.50 mg/mL ursolic acid and 0.25 mg/mL biochanin A. Among them betulinic acid showed the best anthelmintic effect with a mortality time of (3.40 ± 0.66) h.⁷⁹Aerial shoot extract tested against Hymenolepis diminuta, at a dose concentration of 200 and 500 mg/kg, decreased the faecal egg 47.72% and 54.59% respectively.⁸⁰

Ficus insipida: The latex was tested against Colossoma macropomum gills, immobilization of the parasite occurred after 4h on treatment with 250 µL/L of latex and with 500 µL/L, immobilization occurred after 2 h.⁸¹

Cucurbita maxima: the peel extract was tested against Pheritima posthuma, at a concentration of 50 mg/mL, the paralysis time of the earthworm took place in (90 ± 2) min and the death time of the earthworm was (11 ± 2) min.⁸²

Trachyspermum ammi: for aqueous extract, LC₅₀ value was found at 0.1698 mg/mL and for methanolic extract, LC₅₀ values was found at 0.1828 mg/mL.⁷⁵The seeds extract of the plant was also tested against GIT nematodes, showed activity at a dose of 3 g/kg, the maximum reduction in egg count occurred.⁸³

Syzygium aromaticum: the ethanolic extract, tested against Pheritma posthuma, at a dose 2.5 mg/mL, causing paralysis of the worm in (4.27 ± 0.25) min and death within (45.00 ± 2.00) min. At 5mg/mL, the paralysis in (2.43 ± 0.31) min and death occurred within (35.00 ± 4.35) min.⁸⁴ When tested against Cotylophoron cotylophorum, ethanolic extract at 0.5 mg/mL, showing motility (86.27%) after 8 h of treatment.⁸⁵

Trichilia claussenii: anthelmintic activity of the plant Trichilia claussenii was studied against gastrointestinal nematodes, methanol extract of leaves showed a significant LC₅₀ value at 263.8 μg/mL and LC₉₉ value at 522.5 μg/mL.⁸⁶

Withania somnifera: crude extracted hydro-alcoholic solution tested against Pheritima posthuma at dose concentration of 20 and 40 mg/mL, paralysis was shown in (6.5 ± 0.5) min and (2.8 ± 0.8) min and death occurred (13.9 ± 1.2) min and (7.1 ± 0.9) min respectively.⁸⁷

Pleurospermum amabile: the crude methanolic extract when tested against whipworms and blood flukes, bergapten showed an IC₅₀ value 8.6 μg/mL against S. mansoni and 10.6 μg/mL against T. muris.⁸⁸

Macleaya cordata: the crude extract when treated against Toxocara canis, Sanguinarine was showed IC₅₀ value 58 μΜ after 24 h.⁸⁹

Ajania nubigena: the crude extract was tested against Trichuris muris. Linalool and Luteolin were showed IC₅₀ value 20.4 μg/mL and 9.7 μg/mL, respectively after 12 h.⁸⁹

Leucaena leucocephala: the crude extract was tested against C. elegans. Mimosine was showed an IC₅₀ value 16.8 μΜ after 24 h.⁸⁹ The EC50 value cotyledon extract was 0.48 mg mL^-1 and seed extracts showed EC50 value 0.33 mg/mL. ⁹⁰

Warburgia ugandensis: the crude extract was tested against C. elegans, Mimosine showed mortality after 24 h with IC₅₀ value (70.1 ± 17.5) μΜ against.⁸⁹

Plants having anthelmintic activity are summarized in Table 4.

Table 4.

Plants having anthelmintic activity

Name	Biological sources	Mechanism of action	Chemical constituents
Myrrh	Commiphora myrrha or Commiphora molmol, Family-Burseraceae	Reduces activities of Alanine transminase (ALT) and Aspartate transminase (AST)	Limonene, Eugenol, a-Pinene, Cadinene, Acetic acid, Formic acid etc.56
Tulsi	Ocimum sanctum Linn. Family-Lamiaceae	Causing paralysis of infected parasitic worms or death.	Carvacrol, Caryophyllene, Eugenol, Linalool, Urosolic acid, etc.91
Chinaberry tree	Melia azedarach, Family- Meliaceae	Reacting with free proteins reduces the nutrients availability, thus larval death occurs due to starvation, or React with glycoproteins in the larval cuticle, causing death.	Spathulenol, Quercetin, Astragalin, 1,7,8-Trihydroxy-2-naphtaldehyde etc.92
Papaya	Carica papaya, Family-Caricaceae	Killing the parasite worms by eosinophils, attack on structural protein of parasite nematodes.	Papain, Cystatin, Chymopapain, Ascorbic acid, Tocopherol.93
Black caraway	Nigella sativa, Family-Ranunculaceae	Inhibiting the antioxidant enzymes thus produces a defense mechanism towards the oxidants generated by the parasitic nematode.	Linoleic acid, Oleic acid, Palmitic acid, p-cymene, Carvacrol, Thymol, α-Pinene.94
Sohphlang	Flemingia vestita, Family-Leguminosae	Causing paralysis of infected parasitic worms or death.	Formononetin, Genistein, Daidzein, Pseudobaptigenin.95
Walnut	Juglans regia, Family-Juglandaceae	It binds with the free protein of GIT of the host or interferes in energy generation of helminths, causing death of parasites.	Stearic acid, Palmitic acid, alpha Linolenic acid, Oleic acid, Catechin, Tannins.96
Mimusops	Mimusops elengi, Family-Sapotaceae	Denaturation of proteins, produce defense mechanism, damages reactive oxygen species (ROS) properties.	Ursolic acid, Spinasterol, Taraxerol etc.97
Pomegranate	Punica granatum Family-Punicaceae.	Inhibit transformation of larvae from egg, produce inflammation of epithelial cells by peroxisome proliferator-activated receptors-γ and δ-dependent mechanisms	Ellagic acid, Cyanidin-3-glucose, Pelargonidin-3-glucose etc.98
Embelia	Embelia ribes, Family-Primulaceae	Paralysis of worms and reduces fecal eggs per gram (EPG).	Vanillic acid, Christembine, Cinnamic acid, O-cumaric acid, Embelin.99
Epazote	Chenopodium ambrosioides, Family-Amaranthaceae.	Paralysis of the parasitic worms.	Limonene, α-Terpinene p-Cymene, Camphor Thymol.100
Piliostigma	Piliostigma thonningii, Family-Fabaceae.	It stimulates the neuromuscular junction of the parasite mostly and sometimes its effects to the ganglion and cause larval paralysis.	Alepterolic acid, Anticopalic acid, Clovane-2β,9α-diol etc.101
Asparagus	Asparagus officinalis, Asparagus racemosus, Family-Asparagaceae.	Causing paralysis of infected parasitic worms or death.	Racemosol, Asparagamine, Folic acid.102
White clover	Trifolium repens, Family-Fabaceae.	Paralysis of worms and reduces EPG.	Rutin, Quercetin, Myricetin Kaempferol.103
Fig	Ficus insipida, Family-Moraceae.	Causing paralysis of infected parasitic worms or death.	Vomifoliol, Dihydrophaseic acid, Dehydrovomifoliol etc.104
Squash	Cucurbita maxima, Family-Cucurbitaceae.	Inhibit transformation of larvae from egg, reduces EPG.	Palmitic acid, Oleic acid, Linoleic acid, β-sitosterol.105
Ajwain	Trachyspermum ammi, Family-Apiaceae or Umbelliferae.	Causing paralysis of infected parasitic worms or death.	Thymol, α-Pinene, α-Terpinene, β-Pinene, γ-terpinene, p-cymene.106
Cinnamon	Cinnamomum zylanicum, Family - Lauraceae.	Inhibition of the parasitic egg hatching inhibits the fourth stage of larvae motility.	Eugenol, Cinnamic acid Cymene, Cinnamate.107
Nutmeg	Myristica fragrans, Family -Myristicaceae.	Causing paralysis by inhibiting acetyl cholinesterase.	Myristicin, Eugenol, Safrole, Terpinene, Myristic acid.108
Elecampane	Inula helenium, Family-Asteraceae.	Inhibitory effects on process of embryo development, paralysis by inhibiting acetylcholinesterase.	Alantolactone, Inulin, Helenin Stearoptene.109
Clausena anisata	Clausena anisata, Family-Rutaceae.	Causing paralysis by inhibiting acetylcholinesterase.	Coumarins, Linalool, Myrcene, Anethole, Lomonene etc.110
Zanthoxylum	Zanthoxylum zanthoxyloides, Family-Rutaceae.	Inhibition of the parasitic egg hatching prevents larvae from migrating.	Lomonine, Citronellal, Myrcene, α-pinene.111
Annona	Annona squamosa, Family-Annonaceae.	Inhibition of the parasitic egg hatching inhibits cell division.	Anonain, OxophoebineIsocorydine, Reticulin.112
False daisy	Eclipta prostrata, Family-Asteraceae.	Causing paralysis of infected parasitic worms or death.	Quercetin, β-Sitosterol, Luteoloside, Apigenin, Luteolin.113
Name	Biological sources	Mechanism of action	Chemical constituents
Turkey berry	Solanum torvum, Family-Solanaceae.	Causing paralysis of infected parasitic worms, or reduces EPG.	Quercetin, Isoquarecetin Kaempferol, Rutin etc.114
Myrobalan	Terminalia chebula, Family -Combretaceae.	Interrupts in energy production by binds free protein from GI tract or oxidative phosphorylation.	Arjungenin, Chebulin, Ellagic acid, Chebulic acid, Gallic acid.115
Vinca	Catharanthus roseus, Family-Apocynaceae	Prevents polymerization of tubulin into microtubules.	Vincristine, Vinblastine Catharanthine etc.116
Celandine	Chelidonium majus, Family-Papaveraceae	Reduce ROS generation, paralysis the parasitic worms.	Chelidonine, Sanguinarine, Caffeic acid, Protopine.117
Mentha	Mentha cordifolia, Family-Lamiaceae	Causing paralysis of infected parasitic worms or death.	Carvone, Limonene, Menthol.118,8
Sainfoin	Onobrychis viciifolia, Family-Fabaceae.	Reduce nematode excretion from GI tract, delay in egg maturation.	Tannin, Rutin, Nicotiflorin.119
Ashwagandha	Withania somnifera, Family -Solanaceae	Causing paralysis of infected parasitic worms or death.	Withanolides, Anaferine, Sitoindoside.120
Coriander	Coriandrum sativum, Family - Apiaceae	Reduce faecal egg count of worm and also inhibit the egg hatching process.	Linalool, Camphor, Geraniol, Coumarins, Linoleic acid.121

3. CONCLUSIONS

A number of plants/extracts are reported to have anthelmintic activity. Most of the studies reported in vitro activity and only a few studies report in vivo activity. So, more research is needed to investigate the molecular mechanism of action of the reported anthelmintic plants/extracts as well as there is a need to either modify existing anthelmintic agents or explore new molecular targets to get next generation anthelmintic agents.

3.1. Future perspectives

Now a days novel anthelmintic targets like lysine deacetylases, lysine deacetylases, KDAC inhibitors, kinase inhibitors are explored. Modification of chemical structure and combination of known anthelmintics is also one of the ways to combat this challenge. Drug repurposing is also an emerging trend in anthelmintic drug discovery e.g. trichlorfon, a broad-spectrum organophosphorus insecticide has recently proved as anthelmintic agent.