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. 2022 Nov 4;27(21):7579. doi: 10.3390/molecules27217579

Antileishmanial Activities of Medicinal Herbs and Phytochemicals In Vitro and In Vivo: An Update for the Years 2015 to 2021

Abdalla A Hassan 1, Hassan E Khalid 1,*, Abdelwahab H Abdalla 2, Maowia M Mukhtar 3, Wadah J Osman 1,4, Thomas Efferth 5,*
Editor: Jolanta Sereikaitė
PMCID: PMC9656935  PMID: 36364404

Abstract

Leishmaniasis is one of the most neglected tropical diseases that present areal public health problems worldwide. Chemotherapy has several limitations such as toxic side effects, high costs, frequent relapses, the development of resistance, and the requirement for long-term treatment. Effective vaccines or drugs to prevent or cure the disease are not available yet. Therefore, it is important to dissect antileishmanial molecules that present selective efficacy and tolerable safety. Several studies revealed the antileishmanial activity of medicinal plants. Several organic extracts/essential oils and isolated natural compounds have been tested for their antileishmanial activities. Therefore, the aim of this review is to update and summarize the investigations that have been undertaken on the antileishmanial activity of medicinal plants and natural compounds derived, rom plants from January 2015 to December 2021. In this review, 94 plant species distributed in 39 families have been identified with antileishmanial activities. The leaves were the most commonly used plant part (49.5%) followed by stem bark, root, and whole plant (21.9%, 6.6%, and 5.4%, respectively). Other plant parts contributed less (<5%). The activity was reported against amastigotes and/or promastigotes of different species (L. infantum, L. tropica, L. major, L. amazonensis, L. aethiopica, L. donovani, L. braziliensis, L. panamensis, L. guyanensis, and L. mexicana). Most studies (84.2%) were carried out in vitro, and the others (15.8%) were performed in vivo. The IC50 values of 103 plant extracts determined in vitro were in a range of 0.88 µg/mL (polar fraction of dichloromethane extract of Boswellia serrata) to 98 µg/mL (petroleum ether extract of Murraya koenigii). Among the 15 plant extracts studied in vivo, the hydroalcoholic leaf extract of Solanum havanense reduced parasites by 93.6% in cutaneous leishmaniasis. Voacamine extracted from Tabernaemontana divaricata reduced hepatic parasitism by ≈30 times and splenic parasitism by ≈15 times in visceral leishmaniasis. Regarding cytotoxicity, 32.4% of the tested plant extracts against various Leishmania species have a selectivity index higher than 10. For isolated compounds, 49 natural compounds have been reported with anti-Leishmania activities against amastigotes and/or promastigotes of different species (L. infantum, L. major, L. amazonensis, L. donovani and L. braziliensis). The IC50 values were in a range of 0.2 µg/mL (colchicoside against promastigotes of L. major) to 42.4 µg/mL (dehydrodieuginol against promastigotes of L. amazonensis). In conclusion, there are numerous medicinal plants and natural compounds with strong effects (IC50 < 100 µg/mL) against different Leishmania species under in vitro and in vivo conditions with good selectivity indices (SI > 10). These plants and compounds may be promising sources for the development of new drugs against leishmaniasis and should be investigated in randomized clinical trials.

Keywords: Leishmania, medicinal plant, natural product, neglected tropical disease, phytotherapy, pharmacognosy, promastigotes

1. Introduction

Leishmaniasis is a group of diseases caused by protozoa parasites from more than 20 Leishmania species. In 2018, 92 countries and 83 territories were considered endemic for Leishmania species or had previously reported cases of cutaneous and visceral leishmania, respectively. Today, more than 1 billion people live in areas endemic to leishmaniasis and are at risk of infection. An estimated 30,000 new cases of visceral leishmania and more than 1 million new cases of cutaneous leishmania occur annually [1]. The parasite is categorized into two main groups: Old World leishmaniasis, which is endemic in Africa, Asia, the Mediterranean, and the Middle East. Leishmania tropica, L. major, L. aethiopica, and L. donovani are the four common species causing Old World leishmaniasis. New World leishmaniasis is caused by L. mexicana, L. amazonensis, L. braziliensis, L. panamensis, L. peruviana, L. guyanensis, L. pifanoi, L. venezuelensis, L. shawi, and L. lainsoni [2]. There are three clinical forms of leishmaniasis in humans: namely, cutaneous, mucocutaneous and visceral leishmaniasis. Cutaneous leishmaniasis is a less severe form of the disease which usually manifests in self-healing ulcers. Mucocutaneous leishmaniasis results in disfiguring lesions of mucous membranes in the nose, mouth, and throat. Visceral leishmaniasis is the most severe form of the disease which can result in 95% mortality of infected patients if not treated [3].

In 2020, more than 90% of new cases of visceral leishmaniasis reported to the WHO occurred in Bangladesh, Brazil, China, Ethiopia, Eritrea, India, Kenya, Somalia, South Sudan, Sudan, and Yemen [1]. Over 90% of mucocutaneous leishmaniasis occurred in Bolivia, Brazil, Ethiopia, and Peru, and more than 85% of cutaneous leishmaniasis cases appeared in Afghanistan, Algeria, Brazil, Colombia, Iran, Libya, Pakistan, Peru, Syria, and Tunisia [1]. Depending on the stage of its life cycle, the parasite exhibits two morphological forms in its life cycle: The amastigotes in macrophages of the mammalian host and the promastigotes in the gut of the sand fly vectors. The life cycle of the Leishmania parasite starts if a parasitized female sand fly takes a blood meal from a vertebrate host to produce its eggs. As the sand fly feeds, infective promastigotes enter the vertebrate host via the insect’s proboscis. The promastigotes are then phagocytosed by macrophages which they transform into amastigotes and reproduce by binary fission. They increase in number until the cell eventually bursts and then infects other phagocytic cells to continue the cycle [4]. Over the years, a number of drugs have been employed for the treatment of leishmaniasis. A brief account of the mechanism of action and mode of administration of these drugs has been presented in Table 1 [5].

Table 1.

Drugs used for the treatment of leishmaniasis.

Name of the
Drug		 Mode of Action Mode of
Administration		 Adverse Effects
Pentavalent
antimonials		 Inhibition of glycolysis and β-oxidation of fatty acids of parasite Intralesional for CL, Parenteral Abdominal pain, erythema, nausea, toxicity (hepatic, pancreas, renal, muscular, and skeletal
cardiothrombocytopenia or leukopenia)
Amphotericin B Binding to parasite’s membrane sterols and changing its permeability selective to K+ and Mg2+ Liposomal
formulations,
Deoxycholate
formulations		 Fever, nausea, hypokalemia, anorexia, leukopenia, kidney failure, and heart problems
Pentamidine Interferes with DNA synthesis and modifies the morphology of kinetoplast Parenteral,
Intramuscular
administration		 Pain, nausea, vomiting, dizziness, myalgia, hypertension, headache, hypoglycemia, and transient hyperglycemia
Miltefosine Associated with phospholipid biosynthesis and alkyl-lipid metabolism in leishmania Oral for VL Nausea, vomiting, diarrhea, and raised creatinine
Paromomycin Inhibition of protein biosynthesis in sensitive organism Topical for CL
Parenteral for VL		 Erythema, pain, edema, and ototoxicity (damage to the internal ear)
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Latest developments in the prevention and treatment regarding a permanent solution for leishmaniasis in terms of successful human vaccination is still a major challenge. However, there are different vaccinations currently being tested in mouse models. One of them uses “killed but metabolically active” parasites to induce host immune system reaction. Using salivary peptides of the sandfly holds the potential to be used as a vaccine component. However, the complex immune response makes it a challenge [6]. Macrophage-targeted drug delivery systems are another novel approach to directly affect Leishmania parasites that live in the macrophages. As getting into macrophages is a challenge, liposomes, microspheres, nanoparticles, and carbon nanotubes are some of the various drug carriers that are studied to target macrophages. In addition, the use of specific receptors expressed by macrophages to actively deliver a drug is also used [7].

The current treatment by chemical drugs has several limitations such as toxic side effects, high costs, frequent relapses, the development of resistance, and the requirement for long-term treatment [8,9]. Thus, investments in novel drug development against this parasitic disease may be a risky affair. Medicinal plants are centuries-old sources in the various traditional herbal medicine systems of the world. For instance, their importance lies in the fact that the WHO concludes that about 80% of the world’s population relies on them for primary health care [10]. Moreover, 25 to 50% of the pharmacopeias worldwide contain plant products and drugs derived from natural products [11]. Therefore, current research approaches for the treatment of leishmaniasis should largely consider medicinal plants as an important area of search.

The aim of this review is to update and summarize the investigations that have been undertaken on the antileishmanial activity of medicinal plants and natural compounds derived from plants from January 2015 to December 2021.

2. Results

As shown in Table 2, 92 plant species distributed in 39 families have been identified with anti-Leishmania activities. The family Fabaceae accounted for the highest percentage (9.7%) followed by Asteraceae (7.6%). Lamiaceae and Solanaceae account for 6.5% each.

Table 2.

Botanical characteristics of the medicinal herbs in the present study.

No Family Name Scientific Name Part Used
1. Anacardiaceae Pistacia lentiscus Leaves
Schinus terebinthifolia Fruits
Schinus molle Leaves
Spondias mombin Leaves
2. Annonaceae Annona senegalensis Stem bark
Bocageopsis multiflora Leaves
Guatteria latifolia Branch
Cleistopholis patens Stem bark
3. Apiaceae Ferula communis Whole plant
4. Apocynaceae Tabernaemontana divaricata Voacamine
Mondia whitei Roots
Pentalinon andrieuxii Pentalinon sterol
5. Araliaceae Oreopanax floribundus Leaves
6. Arecaceae Phoenix dactylifera Kernel and date fruit
7. Asteraceae Acanthospermum hispidum Whole plant
Tessaria integrifolia Leaves
Abuta grandifolia Leaves
Cynara scolymus Leaves
Artemisia absinthium Leaves
Artemisia campestris Leaves
Artemisia herba-alba Aerial parts, Leaves
Bidens pilosa Whole plant
Tessaria integrifolia Whole plant
8. Balanophoracea Thonningia sanguinea Whole plant
9. Bignoniaceae Handroanthus serratifolius Lapachol
Jacaranda glabra Bark
10. Burseraceae Boswellia serrata Resin
11. Cannabaceae Celtis australis Leaves
12. Capparaceae Capparis spinosa Fruits
13. Cistaceae Citrus sinensis Leaves
14. Combretaceae Terminalia ivorensis Leaves
15. Cupressaceae Juniperus excelsa Leaves, fruits
16. Ericaceae Arbutus unedo Leaves
Erica arborea Flower
17. Euphorbiaceae Bridelia ferruginea Leaves
Ejije bidu Leaves
Croton caudatus Leaves
18. Fabaceae Afzelia africana Stem bark
Baphia nitida Stem bark
Cassia alata Leaves
Cassia gloca Leaves
Cassia sieberiana Roots, leaves
Prosopis laevigata Leaves
Parkia clappertoniana Stem bark, leaves
Tamarindus indica Leaves
Prosopis juliflora Leaves
19. Gentianaceae Anthocleista nobilis Leaves, stem bark, root
Centaurium erythraea Flowering, stems
20. Lamiaceae Marrubium vulgare Leaves
Mentha pulegium Leaves
Otostegia integrifolia Whole plant
Rosmarinus officinalis Leaves
Salvia clandestina Aerial parts
Vitex fosteri Stem bark, leaves
21. Lauraceae Aniba riparia Fruits
Persea ferruginea Leaves
Cinnamomum cassia Bark
22. Loranthaceae Loranthus europaeus Aerial part
23. Malvaceae Ceiba pentandra Stem bark
Cola acuminata Stem bark
Cola cordifolia Stem bark, leaves
Glyphaea brevis Leaves
24. Marantaceae Thalia geniculata Roots
Iresine diffusa Flower
25. Meliaceae Khaya grandifoliola Stem bark
Cedrela spp Bark
Azadirachta indica Leaves
26. Moraceae Treculia africana Stem bark
Ficus capensis Stem bark, leaves
27. Myrtaceae Eugenia uniflora Leaves, seed
28. Ochnaceae Lophira lanceolata Stem bark, roots
29. Olacaceae Ximenia americana Stem and twigs
30. Papaveraceae Argemone mexicana Aerial parts
31. Piperaceae Piper pseudoarboreum Leaves
32. Rhamnaceae Ziziphus spina-christi Whole plant
33. Rosaceae Pyrus communis Leaves
Pyrus pashia Leaves
Prunus armeniaca Leaves
Eryobotrya japonica Leaves
34. Rubiaceae Mitragyna inermis Stem bark, leaves
Psychotria buhitenii Leaves
35. Rutaceae Zanthoxylum zanthoxyloides Roots, stem bark
Murraya koenigii Stem bark
Clausena anisata Roots
36. Scrophulariaceae Scoparia dulcis Aerial part
Licania salicifolia Leaves
37. Solanaceae Solanum havanense Leaves
Solanum lycocarpum Leaves
Solanum myriacanthum Leaves
Solanum nudum Leaves
Physalis angulata Flowers
Solanum seaforthianum Leaves
38. Urticaceae Urtica dioica Leaves
39. Verbenaceae Lantana camara Leaves
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The leaves were the most commonly used plant part as compared to other parts (49.5%) followed by stem bark, roots, and whole plant (21.9%, 6.6%, and 5.4%, respectively). Aerial parts and fruits accounted for 4.5% each. Other plant parts (flowers, seeds, resins, branches, and kernels) contributed less (<4%) (Figure 1).

Figure 1.

Figure 1

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Fraction of plant parts used in anti-Leishmania studies.

With respect to the test methods, 84.2% of studies were carried in vitro, while 15.8% of them were performed using in vivo assays (Table 3 and Table 4). For in vitro assay, 80 medicinal plants were screened in vitro for antileishmanial activities against different Leishmania species (L. infantum, L. tropica, L. major, L. amazonensis, L. aethiopica, L. donovani, L. braziliensis, L. panamensis, L. guyanensis, and L. mexicana) and life cycle forms (amastigotes and/or promastigotes). The IC50 value of 103 plant extracts/essential oils determined in vitro was in a range of 0.88 µg/mL (polar fraction of dichloromethane extract of Boswellia serrata) to 98 µg/mL (petroleum ether extract of Murraya koenigii) (Table 3). B. serrata (resins), R. officinalis (leaves), A. riparia (fruits), M. pulegium (leaves) as extracts had strong anti-Leishmania activity (0.88, 1.2, 1.3, and 1.3 µg/mL, respectively).

Table 3.

Anti-Leishmania activity of medicinal plants in vitro.

No. Scientific Name Organism Stage Part Used Most Active Extract/
Essential Oil		 IC50 (µg/mL) Bioactive

Compounds 		Data Analysis
(Activity)		 Reference
1. Abuta
grandifolia 		L. amazonensis Promastigotes Leaves Ethanol 38.1 Alkaloids, triterpenes, saponins Moderate [12]
L. braziliensis 31.1 Moderate
2. Acanthospermum hispidum L. donovani Promastigotes Whole plant 50% aqueous ethanol 32.10 Essential oil, alkaloids Moderate [13]
3. Afzelia africana L. donovani Promastigotes Stem bark 50% aqueous ethanol 77.10 Alkaloids, tannins,
flavonoids, saponins		 Weak [13]
4. Aniba riparia L. amazonensis
Amastigotes Fruits 50% aqueous ethanol 1.30 Riparin E High [14]
Promastigotes 4.70 High
5. Annona
senegalensis 		L. donovani Promastigotes Leaves 50% aqueous ethanol 10.80 Alkaloids, tannins,
flavonoids, saponins, terpenoids, glycosides		 Moderate [13]
Stem bark 27.80 Moderate
6. Anthocleista
nobilis 		L. donovani Promastigotes Leaves 50% aqueous ethanol 41.50 Glycosides, saponins, steroids Moderate [13]
Root 79.0 Anthocleistol Weak
7. Arbutus unedo L. infantum Promastigotes Leaves n-Hexane 64.05 Phenolics, flavonoids Weak [15]
L. tropica 79.57 Weak
8. Argemone
mexicana 		L. donovani Promastigotes Aerial part Petroleum ether 50.0 - Moderate [16]
9. Artemisia
absinthium 		L. major Promastigotes Leaves Hydrodistillation 1.49 Essential oil High [17]
10. Artemisia
campestris 		L. major Promastigotes Leaves Hydrodistillation 2.20 Essential oil High [17]
11. Artemisia herba-alba L. major Promastigotes Leaves Hydrodistillation 1.20 Essential oil High [17]
12. Artemisia herba-alba L. infantum. Amastigote Aerial part Methanol extract 68.25 -

 Weak [18]
L. major 37.87 Moderate
L. infantum Promastigotes 77.97 Weak
L. major 55.21 Weak
13. Azadirachta
indica 		L. infantum Amastigotes Leaves Oil 15.3 Phenolics,
flavonoids		 Moderate [19]
L. tropica 17.6 Moderate
14. Baphia nitida L. donovani Promastigotes Stem-bark 50% aqueous ethanol 34.40 Tannins, flavonoids, saponins, glycosides Moderate [13]
15. Bidens pilosa L. donovani Promastigotes Whole plant 50% aqueous ethanol 28.90 Essential oil, flavonoids, alkaloids, saponins, triterpenes Moderate [13]
16. Bocageopsis multiflora L. amazonensis Promastigotes
 Leaves Ethanol 37.9 Essential oil, alkaloids Moderate [12]
L. braziliensis 19.1 Moderate
17. Boswellia
serrata 		L. donovani Amastigotes Resin Polar fractions of
dichloromethane		 0.88 Boswellic acids High [20]
18. Bridelia
ferruginea 		L. donovani Promastigotes Leaves 50% aqueous ethanol 16.50 Flavonoids, tannins, triterpenoids Moderate [13]
19. Capparis
spinosa 		L. tropica Promastigotes Fruits Methanol 44.6 Tannins, alkaloids,
saponins, terpenoids, glycosides		 Moderate [21]
Aqueous 28.5 Moderate
20. Cassia alata L. donovani Promastigotes Leaves 50% aqueous ethanol 10.10 Flavonoids, glycosides Moderate [22]
21. Cassia gloca L. tropica Promastigotes Leaves Methanol 9.62 Flavonoids High [22]
22. Cassia
sieberiana 		L. donovani Promastigotes Leaves 50% aqueous ethanol 62.90 Flavonoids, alkaloids Weak [23]
23. Cedrela spp. L. amazonensis Promastigotes Bark Ethanol 36.8 Sesquiterpenes,
triterpenes		 Moderate [22]
L. braziliensis 18.2 Moderate
24. Ceiba pentandra L. donovani Promastigotes Stem bark 50% aqueous ethanol 31.10 Isoflavones,
sesquiterpenoids		 Moderate [13]
25. Centaurium
erythraea 		L. tropica Promastigotes Flowering stems n-Hexane 37.20 Phenolics, flavonoids Moderate [23]
L. major 64.52 Weak
26. Celtis australis L. tropica Promastigotes Leaves Methanol 69.13 Flavonoids Weak [22]
27. Cistus crispus L. major Promastigotes Leaves Methanol 84.29 Phenolics, flavonoids Weak [15]
L. infantum n-Hexane 82.39 Weak
L. tropica 96.82 Weak
L. major 47.29 Moderate
28. Citrus sinensis L. tropica Promastigotes Leaves Methanol 12.27 Flavonoids Moderate [22]
29. Cola acuminata L. donovani Promastigotes Stem bark 50% aqueous ethanol 47.80 Purine alkaloids,
catechins, (tannins)		 Moderate [13]
30. Cola cordifolia L. donovani Promastigotes Stem bark 50% aqueous ethanol 25.10 Tannins, phenolics Moderate [13]
Leaves 18.20 Moderate
31. Clausena
anisata 		L. donovani Promastigotes Roots 50% aqueous ethanol 12.10 Essential oil, indole
alkaloids, coumarins		 Moderate [13]
32. Cleistopholis patens L. donovani Promastigotes Stem bark 50% aqueous ethanol 60.20 Flavonoids, saponins, alkaloids Weak [13]
33. Croton
caudatus 		L. donovani Promastigotes Leaves Ethyl acetate –hexane (9:1) 10.0 Terpenoids High [23]
Amastigote 2.5 High
34. Cynara
scolymus 		L. tropica Promastigotes Stem leaf Ethanol 80.0 - Weak [24]
35. Ejije bidu L. amazonensis Promastigotes Leaves Ethanol 17.8 - Moderate [12]
L. braziliensis 13.3 Moderate
36. Erica arborea L. major Promastigotes Flower Methanol 43.98 - Moderate [18]
L. infantum. 61.27 Weak
L. major Amastigotes 36 Moderate
L. infantum. 53.93 Weak
37. Eryobotrya
japonica 		L. tropica Promastigotes Leaves Methanol 10.59 Flavonoids Moderate [22]
38. Eugenia
uniflora 		L. amazonensis Amastigotes Leaves n-Hexane 9.20 Sesquiterpenes,
flavonoids		 High [25]
L. donovani Promastigotes Seeds 50% aqueous ethanol 26.60 Essential oil, flavonoids, tannins Moderate [13]
39. Ferula
communis 		L. aethiopica Promastigotes Whole parts 80% methanol 11.38 Phenolics, flavonoids Moderate [26]
L. donovani 23.41 Moderate
L. aethiopica Amastigotes 14.32 Moderate
L. donovani 31.12 Moderate
40. Ficus capensis L. donovani Promastigotes Stem bark 50% aqueous ethanol 37.0 Alkaloids, phenolics, flavonoids Moderate [13]
Leaves 88.90 Weak
41. Glyphaea brevis L. donovani Promastigotes Leaves 50% aqueous ethanol 43.40 Tannins, alkaloids,
flavonoids		 Moderate [13]
42. Guatteria
Latifolia 		L. amazonensis Promastigote Branch n-hexane fraction of ethanol 51.7 Alkaloids Weak [27]
43. Iresine diffusa L. amazonensis Promastigotes
 Flower Ethanol 30.5 Sesquiterpenes,
triterpenes		 Moderate [12]
L. braziliensis 11.1 Moderate
44. Jacaranda
Glabra 		L. amazonensis Promastigotes Bark Ethanol 29.8 - Moderate [12]
L. braziliensis 17.4 Moderate
45. Khaya
grandifolia 		L. donovani Promastigotes Stem bark 50% aqueous ethanol 43.20 Alkaloids, saponins, tannins Moderate [13]
46. Lantana camara L. amazonensis Amastigotes Leaves Dichloromethane 21.8 Terpenoids Moderate [28]
47. Licania
Salicifolia 		L. panamensis Amastigotes Leaves Ethyl acetate 9.8 Triterpenes, flavonoids High [29]
48. Lophira
lanceolata 		L. donovani Promastigotes Stem bark 50% aqueous ethanol 68.60 Flavonoids, saponins, alkaloids Weak [13]
Roots 66.0 Alkaloids Weak
49. Marrubium vulgare L. infantum Amastigotes Leaves Methanol 18.64 - Moderate [18]
L. major 32.15 Moderate
L. infantum Promastigotes 35.63 Moderate
L. major 45.84 Moderate
50. Mentha pulegium L. infantum Promastigotes Leaves Essential oil 2.0 Menthone, pulegone High [30]
L. tropica 2.2 High
L. major 1.30 High
51. Mitragyna
Inermis 		L. donovani Promastigotes Leaves 50% aqueous ethanol 21.90 Indole alkaloids, triterpenoids Moderate [13]
Stem bark 28.0 Moderate
52. Mondia whitei L. donovani Promastigotes Roots 50% aqueous ethanol 31.0 Glycosides Moderate [13]
53. Murraya
koenigii 		L. donovani Promastigotes Stem Petroleum ether 98.0 - Weak [16]
54. Oreopanax
floribundus 		L. panamensis Amastigotes Leaves Dichloromethane 24.6 Triterpenes Moderate [29]
Ethyl acetate 23.7 Triterpenes, flavonoids Moderate
55. Otostegia
integrifolia 		L. aethiopica Promastigotes
Amastigotes		 Whole parts 80% methanol 13.03 Phenolics, flavonoids Moderate [31]
L. donovani 17.24 Moderate
L. aethiopica 16.84 Moderate
L. donovani 14.55 Moderate
56. Parkia
clappertoniana 		L. donovani Promastigotes Leaves 50% aqueous ethanol 17.0 Saponins, flavonoids, Tannins Moderate [13]
Stem bark 17.60 Saponins, steroids, triterpenes Moderate
57. Persea ferruginea L. panamensis Amastigotes Leaves Ethyl acetate 25.5 Triterpenes, leucoanthocyanidins, coumarins Moderate [29]
58. Phoenix
dactylifera 		L. major Promastigotes kernel Methanol 23.0 Gallic acid Moderate [32]
59. Physalis
angulata 		L. amazonensis Promastigotes Flower Ethanol 17.6 Terpenes, phenolic
acids, flavonoids		 Moderate [12]
L. braziliensis 43.5 Moderate
60. Piper
pseudoarboreum 		L. amazonensis Promastigotes
 Leaves Ethanol 31.4 Alkamides Moderate [33]
L. braziliensis 21.3 Moderate
L. guyanesis 41.3 Moderate
L. infantum 32.3 Moderate
61. Pistacia
lentiscus 		L. infantum Promastigotes Leaves Essential oil 11.28 Myrcene, α-pinene Moderate [23]
L. tropica 23.50 Moderate
L. major 17.52 Moderate
L. infantum Fruits Essential oil 8.0 Limonene
α-pinene		 High
L. tropica 26.20 Moderate
L. major 21.42 Moderate
62. Rosmarinus
officinalis 		L. infantum Promastigotes Leaves Essential oil 1.20 α-Pinene, 1,8-cineole, borneol High [23]
L. tropica 3.50 High
L. major 2.60 High
63. Prosopis
juliflora 		L. donovani Promastigotes Leaves Methanol 3.12 Saponins, tannins,
flavonoids, alkaloids		 High [34]
64. Prosopis
laevigata 		L. amazonensis Amastigotes Leaves Aqueous 35.2 Alkaloids,
anthraquinones		 Moderate [28]
65. Prunus
armeniaca 		L. tropica Promastigotes Leaves Ethanol 16.18 Alkaloids, phenolics, tannins, flavonoids,
terpenoids, coumarins		 Moderate [35]
66. Psychotria buhitenii L. panamensis Amastigotes Leaves Dichloromethane 21.5 Triterpenes, flavonoids Moderate [29]
Ethyl acetate 14.1 Triterpenes, saponins, Coumarins, anthocyanins Moderate
Ethanol 29.4 Saponins, phenolics, tannins, coumarins,
anthocyanins		 Moderate
67. Pyrus
communis 		L. tropica Promastigotes Leaves Ethanol 56.68 Alkaloids, phenolics, tannins, flavonoids,
terpenoids, quinones, saponins		 Weak [35]
68. Pyrus pashia L. tropica Promastigotes Leaves Ethanol 60.95 Alkaloids, phenolics, tannins, flavonoids,
terpenoids, quinones, saponins		 Weak [35]
69. Salvia
clandestina 		L. infantum Promastigotes Aerial part n-Hexane 14.11 - Moderate [36]
L. infantum Dichloromethane 31.57 Moderate
L. tropica 33.77 Moderate
L. major 24.56 Moderate
70. Schinus molle L. amazonensis Amastigotes Leaves Dichloromethane 25.9 Terpenoids Moderate [28]
Dichloromethane: Methanol (1:1) 21.8 Terpenoids, phenolics Moderate
71. Schinus
terebinthifolia 		L. amazonensis Promastigotes Fruits n-Hexane 13.90 Triterpenes Moderate [29]
72. Scoparia dulcis L. amazonensis Promastigotes Aerial part Ethanol 23.9 Diterpenes, triterpenes, flavonoids Moderate [12]
L. braziliensis 25.1 Moderate
73. Spondias mombin L. donovani Promastigotes Leaves 50% aqueous ethanol 81.50 - Weak [13]
74. Tamarindus
indica 		L. donovani Promastigotes Leaves 50% aqueous ethanol 58.12 Phenolics, flavonoids Weak [13]
75. Terminalia ivorensis L. donovani Promastigotes Leaves 50% aqueous ethanol 24.90 Terminolic acid,
quercetin, β-glycyrrhetinic acid		 Moderate [13]
76. Tessaria
integrifolia 		L. amazonensis Promastigotes Leaves Ethanol 54.20 Sesquiterpenes,
flavonoids		 Weak [12]
L. braziliensis 31.60 Moderate
77. Thalia
geniculata 		L. amazonensis Promastigotes Roots Ethanol 29.8 Phytosterols Moderate [12]
L. braziliensis 17.4 Moderate
78. Thonningia sanguinea L. donovani Promastigotes Whole plant 50% aqueous ethanol 18.60 Alkaloids, tannins,
flavonoids		 Moderate [13]
79. Treculia
africana 		L. donovani Promastigotes Stem bark 50% aqueous ethanol 44.80 Catechin, cyanidin
glycosides		 Moderate [13]
80. Vitex fosteri L. donovani Promastigotes Leaves 50% aqueous ethanol 72.40 Essential oil, flavonoids Weak [13]
Stem bark 49.80 Moderate
81. Ximenia
americana 		L. donovani Promastigotes Stem and twigs 50% aqueous ethanol 36.10 Tannins, flavonoids,
alkaloids		 Moderate [13]
82. Zanthoxylum zanthoxyloides L. donovani Promastigotes Roots 50% aqueous ethanol 13.50 Alkaloids, tannins,
flavonoids, essential oil		 Moderate [13]
Stem bark 45.20 Moderate
83. Ziziphus
spina-christi 		L. major Amastigotes Leaves Methanol 54.6 Tannins, flavonoids, Glycosides, alkaloids, terpenoids Moderate [37]
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Table 4.

Anti-Leishmania activity of medicinal plants in vivo.

No. Plant Species Leishmania Species Route, Dose, and Scheme of Treatment Efficacy Bioactive Compounds Reference
1. Cinnamomum cassia Visceral leishmaniasis (L. donovani) Oral: 100 mg/kg/d for 10 days Reduction of hepatic parasitism by 80.9% and splenic parasitism by 82.9% Cinnamaldehyde and its derivatives [38]
2. Croton caudatus Visceral leishmaniasis (L. donovani) Oral: 5 mg/kg/d five
consecutive days		 Reduction of hepatic parasitism by 65% and splenic parasitism by 69.1% Terpenoids [23]
3. Handroanthus serratifolius Cutaneous leishmaniasis
(L. amazonensis) 		Oral: 25 mg/kg/d for 10 days 24.5-fold reduction of parasite number Lapachol [39]
Visceral leishmaniasis (L. infantum) Reduction parasite number in spleen (4.6-fold) and liver (5.3-fold)
4. Loranthus
europaeus 		Cutaneous leishmaniasis (unspecific) Topical: ointment (40%) once daily at bedtime for 6 h under occlusion for maximal 6 weeks 79.0% cure rate without side effects Flavonoids, alkaloids, glycosides, triterpenes, phenolic acids [40]
5. Pentalinon
andrieuxii 		Visceral leishmaniasis (L. donovani) 2.5 mg/kg i.v. Reduction of 64, 83, and 57% of parasites in the liver, spleen, and bone marrow. Pentalinonsterol [41]
6. Piper
pseudoarboreum 		Cutaneous leishmaniasis
(L. amazonensis) 		Intralesional: 25 mg/kg/d for 4 days Reduction of skin lesions by 40% and visceralization by 55%. (E)-Piplartine [33]
7. Prosopis
juliflora 		Visceral leishmaniasis (L. donovani) Oral: 100 mg/kg/d for 21 days 85.1% reduction of parasite number in spleen Saponins, tannins,
flavonoids, alkaloids		 [34]
8. Solanum havanense Cutaneous leishmaniasis
(L. amazonensis) 		Intralesional: 30 mg/kg every 4 days, 5 doses 93.6% reduction of parasite number Steroidal alkaloids,
saponins, phenolics, triterpenes, coumarins		 [42]
9. Solanum
lycocarpum 		Cutaneous leishmaniasis
(L. mexicana) 		Topical: 10 μg/d for 6 weeks 71.4% reduction of parasite number
 Alkaloids (solamargine, solasonine) [43]
10. Solanum
myriacanthum 		Cutaneous leishmaniasis
(L. amazonensis). 		Intralesional: 30 mg/kg every 4 days, 5 doses 56.8% reduction of parasite number Steroidal alkaloids,
saponins, phenolics, triterpenes, coumarins		 [42]
11. Solanum
nudum 		Cutaneous leishmaniasis
(L. amazonensis) 		Intralesional: 30 mg/kg every 4 days, 5 doses 80% reduction of parasite number Steroidal alkaloids,
saponins, phenolics, triterpenes, coumarins		 [42]
12. Solanum seaforthianum Cutaneous leishmaniasis
(L. amazonensis) 		Intralesional: 30 mg/kg every 4 days, 5 doses 49.9% reduction of parasites in treated animals Steroidal alkaloids,
saponins, phenolics, triterpenes, coumarins		 [42]
13. Tabernaemontana divaricata Visceral leishmaniasis (L. donovani) Intraperitoneal: 5 mg/kg twice a week for 3 weeks Decreased the hepatic parasitism by ≈30 times and splenic parasitism by ≈15 times Voacamine [35]
14. Urtica dioica Cutaneous leishmaniasis
(L. major) 		Intramuscular and intralesional: 250 mg/kg for 10 weeks Intralesional treatment reduced lesions more than amphotericin B (control) - [44]
15. Ziziphus spina-christi Cutaneous leishmaniasis (L. major) Topical: 100 and 200 mg/kg/d for 4 weeks Reduction of lesion size by 6.4- and 8.6-fold Tannins, flavonoids, glycosides, alkaloids, terpenoids [37]
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For in vivo assay, among the 15 medicinal plants studied in vivo, the highest activity against cutaneous leishmaniasis was exhibited by the hydroalcoholic leaf extract of Solanum havanense, which reduced parasites by 93.6%, and the highest activity against visceral leishmaniasis was shown by the voacamine compound extracted from Tabernaemontana divaricata, which reduced the hepatic and splenic parasitism by ≈30 times and ≈15 times, respectively (Table 4). For cytotoxic activity, 32.4% of tested plant extracts have good cytotoxic activity with a selectivity index of SI > 10. (Table 5).

Table 5.

Cytotoxic activity and selectivity index of medicinal plants in the present study (p = promastigote; a = amastigote).

No. Plant Species Leishmania
Species		 Part Used Bioactive Extract/
Compounds		 Cytotoxicity
(CC50 µg/mL)		 Selectivity
Index
(CC50/IC50)		 Reference
1. Abuta grandifolia L. amazonensis p Leaves Ethanol 15.2 0.4 [12]
L. braziliensis p 15.6 0.5
2. Acanthospermum hispidum L. donovani p Whole plant 50% aqueous
ethanol		 55.5 1.73 [13]
3. Afzelia africana L. donovani p Stem bark 50% aqueous
ethanol		 232.8 3.02 [13]
4. Aniba riparia L. amazonensis a Fruits 50% aqueous
ethanol		 50.6 38.9 [14]
5. Annona
senegalensis 		L. donovani p Leaves 50% aqueous
ethanol		 273.5 25.32 [13]
Stem bark 127.9 4.60
6. Anthocleista
nobilis 		L. donovani p Leaves 50% aqueous
ethanol		 245.7 5.92 [13]
Root 716.5 9.07
7. Argemone
mexicana 		L. donovani p Aerial part Petroleum ether 52.1 0.95 [16]
8. Artemisia
absinthium 		L. major p Leaves Essential oils 11.22 7.5 [17]
9. Artemisia
campestris 		L. major p Leaves Essential oils 21.12 9.6 [17]
10. Artemisia
herba-alba 		L. major p Leaves Essential oils 11.24 9.4 [17]
11. Artemisia
herba-alba 		L. major p Aerial part Methanol 131.5 2.38 [18]
L. infantum p 131.5 1.86
12. Azadirachta
indica 		L. infantum a Leaves Oil 703.8 46 [19]
L. tropica a 721.6 41
13. Baphia nitida L. donovani p Stem bark 50% aqueous
ethanol		 990.7 28.8 [13]
14. Bidens pilosa L. donovani p Whole plant 50% aqueous
ethanol		 192.8 6.67 [13]
15. Bridelia
ferruginea 		L. donovani p Leaves 50% aqueous
ethanol		 392.9 23.81 [13]
16. Bocageopsis
multifolia 		L. amazonensis p Leaves Ethanol 26.5 0.7 [12]
L. braziliensis p 26.7 1.4
17. Boswellia serrata L. donovani a Resin Polar fractions of dichloromethane 33 38 [20]
18. Capparis spinosa L. tropica p Fruits Methanol 44.6 9.1 [21]
Aqueous 28.5 8.4
19. Cassia gloca L. tropica p Leaves Methanol 1030 - [22]
20. Cassia alata L. donovani p Leaves 50% aqueous
ethanol		 371.5 36.78 [13]
21. Cassia sieberiana L. donovani p Leaves 50% aqueous
ethanol		 62.90 0.77 [13]
22. Cedrela spp. L. amazonensis p Bark Ethanol 66.3 1.8 [12]
L. braziliensis p 67.4 3.7
23. Ceiba pentandra L. donovani P Stem bark 50% aqueous
ethanol		 160.7 3.32 [13]
24. Celtis australis L. tropica p Leaves Methanol 1209 - [22]
25. Cinnamomum cassia L. donovani a Barks Dichloromethane fraction No cytotoxicity at 500 µg/mL - [38]
26. Citrus sinensis L. tropica p Leaves Methanol 1755 - [22]
27. Clausena anisata L. donovani p Roots 50% aqueous
ethanol		 29.2 24.23 [13]
28. Cleistopholis
patens 		L. donovani p Stem bark 50% aqueous
ethanol		 214.9 3.57 [13]
29. Cola cordifolia L. donovani p Stem bark 50% aqueous
ethanol		 465.6 18.55 [13]
Leaves 465.6 25.58
30. Cola acuminata L. donovani p Stem bark 50% aqueous
ethanol		 156.8 3.28 [13]
31. Cynara scolymus L. tropica p Stem leaves Ethanol 40.0 4.96 [24]
32. Ejije bidu L. amazonensis p Leaves Ethanol 133.5 7.5 [12]
L. braziliensis p 133.0 10
33. Erica arborea L. major p Flower Methanol 89.6 2.04 [18]
L. infantum p 89.6 1.46
34. Eryobotrya
japonica 		L. tropica p Leaves Methanol 1903 - [22]
35. Eugenia uniflora L. amazonensis a Leaves n-Hexane 50.5 3.6 [25]
36. Eugenia uniflora L. donovani p Seed 50% aqueous
ethanol		 94.4 3.55 [13]
37. Ferula communis L. aethiopica a, Aerial part 80% methanol 175.22 - [26]
L. donovani a,
38. Ficus capensis L. donovani p Stem bark 50% aqueous
ethanol		 56.6 1.53 [13]
Leaves 257.8 2.90
39. Glyphaea brevis L. donovani p Leaves 50% aqueous
ethanol		 962.2 22.17 [13]
40. Handroanthus serratifolius L. amazonensis p Lapachol Lapachol 3405.8 42.6 [39]
L. infantum p 33.0
41. Iresine diffusa L. amazonensis p Flower Ethanol 39.7 1.3 [12]
L. braziliensis p 11.1 1.7
42. Jacaranda glabra L. amazonensis p Bark Ethanol 18.9 6.4 [12]
L. braziliensis p 191.4 11
43. Khaya
grandifolia 		L. donovani p Stem bark 50% aqueous
ethanol		 50.1 1.16 [13]
44. Lantana camara L. amazonensis a Leaves Aqueous 125.9 >9 [28]
45. Licania salicifolia L. panamensis a Leaves Ethyl acetate >200 >20.4 [29]
46. Lophira
lanceolata 		L. donovani p Stem bark 50% aqueous
ethanol		 45.962 0.67 [13]
Roots 38.9 0.59
47. Marrubium
vulgare 		L. major p Leaves Methanol 107.4 2.34 [18]
L. infantum p 107.2 3.01
48. Mitragyna
inermis 		L. donovani p Leaves 50% aqueous
ethanol		 193.2 8.82 [13]
Stem bark 424.5 15.16
49. Mondia whitei L. donovani p Roots 50% aqueous
ethanol		 434.5 13.97 [13]
50. Murraya koenigii L. donovani p Stem Petroleum ether 73.9 1.32 [16]
51. Oreopanax
floribundus 		L. panamensis a Leaves Dichloromethane 47.4 2.0 [29]
Ethyl acetate 54.1 2.2
52. Otostegia
integrifolia 		L. aethiopica a, Aerial part 80% methanol 144.55 - [26]
L. donovani a,p
53. Parkia
clappertoniana 		L. donovani p Leaves 50% aqueous
ethanol		 112.7 6.63 [13]
Stem bark 42.4 2.41
54. Persea ferruginea L. panamensis a Leaves Ethyl acetate >200 >7.8 [29]
55. Physalis
angulata 		L. amazonensis p Flower Ethanol 19.4 1.1 [12]
L. braziliensis p 17.4 0.4
56. Piper
pseudoarboreum 		L. amazonensis p Leaves Ethanol 55.0 1.8 [33]
L. braziliensis p 2.6
L. guyanesis p 1.3
L. infantum p 1.7
57. Prosopis juliflora L. donovani p Leaves Methanol 0.85 0.26 [34]
58. Prosopis
laevigata 		L. amazonensis a Leaves Dichloromethane 57.0 7 [28]
59. Prunus
armeniaca 		L. tropica p Leaves Ethanol 1912.31 - [44]
60. Psychotria
buhitenii 		L. panamensis a Leaves Dichloromethane 76.8 3.57 [29]
Ethyl acetate 109.5 7.75
Ethanol >200 >6.81
61. Pyrus communis L. tropica p Leaves Ethanol 1411.30 - [35]
62. Pyrus pashia L. tropica p Leaves Ethanol 1230.66 - [35]
63. Schinus molle L. amazonensis a Leaves Dichloromethane 69.7 5 [28]
Dichloromethane: Methanol (1:1) 186.8 6
64. Schinus
terebinthifolia 		L. amazonensis p Fruits n-Hexane 52.0 3.7 [25]
65. Scoparia dulcis L. amazonensis p Aerial part Ethanol 71.7 3.0 [12]
L. braziliensis p 72.8 2.9
66. Solanum
lycocarpum 		L. mexicana a Fruits Solamargine 1515.5 43.3 [43]
Solasonine 1397.9 38.3
67. Spondias mombin L. donovani p Leaves 50% aqueous
ethanol		 55.42 0.68 [13]
68. Tamarindus indica L. donovani p Leaves 50% aqueous
ethanol		 77.9 1.34 [13]
69. Terminalia ivorensis L. donovani p Leaves 50% aqueous
ethanol		 939.2 37.72 [13]
70. Tessaria integrifolia L. amazonensis p Leaves Ethanol 119.2 2.2 [12]
L. braziliensis p 120.0 3.8
71. Thalia geniculata L. amazonensis p Roots Ethanol 50.7 1.7 [12]
L. braziliensis p 50.4 2.9
72. Thonningia sanguinea L. donovani p Whole plant 50% aqueous
ethanol		 286.1 15.38 [13]
73. Treculia africana L. donovani p Stem bark 50% aqueous
ethanol		 172.0 3.84 [13]
74. Urtica dioica L. major p Leaves Aqueous 4500 4.4 [44]
75. Vitex fosteri L. donovani p Leaves 50% aqueous
ethanol		 114.4 1.58 [13]
Stem bark 420.3 8.44
76. Ximenia
americana 		L. donovani p Stem and twigs 50% aqueous
ethanol		 42.3 1.17 [13]
77. Zanthoxylum zanthoxyloides L. donovani p Roots 50% aqueous ethanol 247.1 18.30 [13]
Stem bark 583.5 12.91
78. Ziziphus
spina-christi 		L. major a Leaves Methanol 563.3 10.31 [37]
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For isolated compounds, 49 natural compounds have been identified with anti-Leishmania activities against amastigotes and/or promastigotes of different species (L. infantum, L. major, L. amazonensis, L. donovani and L. braziliensis). The IC50 values were in the range of 0.2 µg/mL (colchicoside against promastigotes of L. major) to 42.4 µg/mL (dehydrodieuginol against promastigotes of L. amazonensis) (Table 6).

Table 6.

Anti-Leishmania activity of isolated natural compounds.

No. Compound Name Leishmania
Species		 Stage Assay Values
(IC50)		 Data Analysis (Activity) Authors
1 2,3-Dihydrobenzofuran L. amazonensis Promastigotes In vitro 1.04 µg/mL High [45]
Amastigotes 1.4 µg/mL High
2 Dehydrodieuginol L. amazonensis Promastigotes In vitro 42.4 µg/mL Moderate [31]
3 Erytro-manassatin A L. amazonensis Promastigotes In vitro 35.4 µg/mL Moderate [46]
Amastigotes 20.4 µg/mL Moderate
4 Threo-manassatin A L. amazonensis Promastigotes In vitro 17.6 µg/mL Moderate [46]
Amastigotes 16.0 µg/mL Moderate
5 Epipinoresinol-4-O-β-D-glucopyranoside L. major Promastigotes In vitro 36.5 µg/mL Moderate [47]
6 Calanolide E1 L. major Promastigotes In vitro 36.5 µg/mL Moderate [48]
7 Calanolide E2 L. major Promastigotes In vitro 29.1 µg/mL Moderate [48]
8 Caffeic acid L. infantum Promastigotes In vitro 12.5 µg/mL Moderate [49]
Amastigotes 21.9 µg/mL Moderate [50]
10 Capsaicin L. infantum Promastigotes In vitro 5.01 µg/mL High [51]
Amastigotes 24.2 µg/mL Moderate
11 Cassine L. amazonensis Promastigotes In vitro 25.2 µg/mL Moderate [52]
12 Spectaline L. amazonensis Promastigotes In vitro 15.8 µg/mL Moderate [52]
13 Berberine L. donovani Promastigotes In vitro 4.8 µg/mL High [53]
14 Colchicoside L. major Promastigotes In vitro 0.2 µg/mL High [54]
Amastigotes 4.0 µg/mL High
15 Bisabolol L. donovani Visceral
leishmaniasis		 In vivo 39.4 µM Moderate [55]
16 2-Demethyl colchicine L. major Promastigotes In vitro 0.5 µg/mL High [54]
Amastigotes 10.2 µg/mL Moderate
17 3-Demethyl colchicine L. major Promastigotes In vitro 0.4 µg/mL High [54]
Amastigotes 11.1 µg/mL Moderate
18 Cornigerine L. major Promastigotes In vitro 0.8 µg/mL High [54]
Amastigotes 11.9 µg/mL Moderate
19 Piperine L. infantum Promastigotes In vitro 3.03 µg/mL High [51]
20 Colchicine L. major Promastigotes In vitro 0.4 µg/mL High [54]
Amastigotes 8.7 µg/mL High
21 N-deacetyl-N-formyl
colchicine		 L. major Promastigotes In vitro 0.5 µg/mL High [54]
Amastigotes 10.2 µg/mL Moderate
22 Colchifoline L. major Promastigotes In vitro 0.7 µg/mL High [54]
Amastigotes 14.0 µg/mL Moderate
23 Demecolcine L. major Promastigotes In vitro 0.7 µg/mL High [54]
Amastigotes 14.8 µg/mL Moderate
24 Staurosporine L. amazonensis Promastigotes In vitro 0.08 µM High [56]
Amastigotes 10.0 µM High
L. donovani Promastigotes 2.1 µM High
25 7-Oxostaurosporine L. amazonensis Promastigotes In vitro 3.6 µM High [56]
Amastigotes 0.1 µM High
L. donovani Promastigotes 0.6 µM High
26 4′-Demethylamine-4′-
oxostaurosporine 		L. amazonensis Promastigotes In vitro 17.1 µM Moderate [56]
Amastigotes 2.0 µM High
27 Streptocarbazole B L. amazonensis
Promastigotes In vitro 10.4 µg/mL Moderate [56]
Amastigotes 2.5 µg/mL High
28 3-O-acetylspectaline L. donovani Promastigotes In vitro 25.9 µg/mL Moderate [53]
29 3-O-acetylcassine L. donovani Promastigotes In vitro 30.3 µg/mL Moderate [53]
30 Soranjidiol L. amazonensis Promastigotes In vitro 16.3 J/cm2 Moderate [57]
31 Epigallocatechin 3-O-
gallate		 L. infantum Visceral
leishmaniasis		 In vivo ED50 = 12.4 mg/kg/day Moderate [58]
32 5-Chlorosoranjidiol L. amazonensis Promastigotes In vitro 13.8 J/cm2 Moderate [58]
33 Bisoranjidiol L. amazonensis Promastigotes In vitro 15.2 J/cm2 Moderate [58]
34 Gallic acid L. major Promastigotes In vitro 23.0 µg/mL Moderate [32]
35 Calanolides E1 L. infantum. Amastigotes In vitro 37.1 µM Moderate [48]
36 Calanolides E2 29.1 µM Moderate
37 Apigenin L. amazonensis Promastigotes In vitro 23.7 µM Moderate [59]
Amastigotes 4.3 µM High
38 2′-hydroxyflavanone L. amazonensis Promastigotes In vitro 20.5 µM Moderate [60]
Amastigotes 3.09 µM High
39 5,7,3′,4′-tetrahydroxy-
6,8-diprenylisoflavone		 L. amazonensis Promastigotes In vitro 2.7 µM High [61]
Amastigotes 1.1 µM High
40 Brachydin B L. braziliensis Promastigotes In vitro 7.05 µM High [62]
41 Brachydin C L. amazonensis Promastigotes In vitro 10.0 µM High [62]
Amastigotes 6.25 µM High
L. braziliensis Promastigotes 8.8 µM High
42 Ursolic acid L. amazonensis Promastigotes In vitro 6.2 µg/mL High [63]
L. donovani Amastigotes 1.8 µM High
43 Aplysulphurin L. donovani Amastigotes In vitro 3.1 µM High [64]
44 Tetrahydroaplysulphurin-1 L. donovani Amastigotes In vitro 3.5 µM High [64]
45 Membranolide L. donovani Amastigotes In vitro 9.7 µM High [64]
46 Apigenin Cutaneous leishmaniasis Cutaneous leishmaniasis In vivo ED50 = 0.73 mg/kg High [65]
47 Darwinolide L. donovani Amastigotes In vitro 11.2 µM Moderate [63]
48 Pukalide aldehyde L. donovani Amastigotes In vitro 1.9 µM High [66]
49 Epigallocatechin 3-O-
gallate		 L. infantum Amastigotes In vitro 2.6 µM High [58]
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Numerous natural compounds were isolated from different parts of the plants that were used in traditional medicine to treat leishmaniasis [67]. These compounds act against Leishmania by various mechanisms including the disintegration of cytoplasmic membranes, electron flow disturbances, active transport of crucial substances, coagulation of the cell contents, and destabilization of proton motive forces [68]. For example:

  • Some medicinal plants are enriched with essential oils composed of different hydrophobic molecules which can diffuse easily across cell membranes and consequently gain access to intracellular targets [67,69]. They may also act on ATPases and other proteins located in cytoplasmic membranes that are surrounded by lipid molecules. They can also cause a distortion of lipid–protein interactions in hydrophobic parts of the proteins, or they can interact with the enzymes involved in the synthesis of structural sections.

  • The diversity of terpenoids increases their biological activity spectrum, including several Leishmania species [70]. Terpenes can easily penetrate the lipid bilayer of the cell membrane and produce changes in the integrity of cell structure and the mitochondrial membrane of Leishmania parasites [67]. For example, Artemisinin induced apoptosis, depolarization of the mitochondrial membrane potential, and DNA fragmentation [71,72]. Ursolic acid induce programmed cell death independent of caspase 3/7 but dependent on mitochondria. The compound reduced the lesion size and parasite load of cutaneous leishmaniasis in vivo [70]. (−)-α-Bisabolol induced phosphatidylserine externalization and caused cytoplasmic membrane damage, both of which are apoptosis indicators. The compound also decreased ATP levels and disrupted the mitochondrial membrane potential [73].

  • Plants enriched with antioxidant compounds such as flavonoids may act by initiating morphological changes and causing a loss of cellular integrity, leading to cell cycle arrest in the G1 phase [59]. They also may act by damaging the mitochondria of the parasites [67]. For example, apigenin increased intracellular reactive oxygen species (ROS) and the number of double-membrane vesicles as well as myelin-like membrane inclusions, which are characteristics of the autophagic pathway. Furthermore, the fusion between autophagosome-like structures and parasitophorous vacuoles was observed [65]. Epigallocatechin 3-O-gallate (EGCG) has increased ROS levels, which decreased the mitochondrial membrane potential and the ATP levels [58].

  • The diversity of structures within the coumarin group enables them to exhibit many biological activities, including anti-Leishmania activity. It represents a promising natural compound that can act on two fronts: as a treatment for leishmaniasis (able to induce mitochondrial membrane damage and changes in ultrastructure [74] and as a tool to control Leishmania vectors (might block the transmission of leishmaniasis since they decrease parasite loads [27].

  • Many alkaloids have been described as having biological activities against trypanosomatids, such as Leishmania spp. For example, heterocyclic steroids (solamargine and solasonine) induced different immunochemical pathways in macrophages and dendritic cells. Additionally, they were capable of enhancing the expression levels of transcription factors, such as NFκB/AP-1 [43]. In addition, isoquinoline alkaloid (berberine) has leishmanicidal activity through a reduction in the viability of promastigotes and the generation of ROS in these cells. It also increased the levels of mitochondrial superoxide and induced the depolarization of mitochondrial transmembrane potential [53].

3. Methods

3.1. Study Design and Setting

In order to perform this review, the following aspects were addressed: identification and selection of the theme of the research question, establishment of criteria for selection of the sampling, the definition of information to be extracted from selected studies, assessment of the studies included in the integrative review, and final explanation of the results.

3.2. Search Strategies

The databases used for this article were PubMed, Google Scholar, Web of Science, Research Gate, SCOPUS, and Scientific Electronic Library Online (SciELO) using the keywords: neglected tropical disease, Leishmania species, anti-Leishmania activity, natural product, medicinal plants, and promastigote form. We used the search terms separately and in combination with the Boolean operators “OR” or “AND”.

3.3. Inclusion and Exclusion Criteria

The initial total articles (1374) were adjusted for the restriction in the year of publication (from 1 January 2015 to 31 December 2021) (806), duplicates (273), articles that were not available in full (67) and articles in other languages (4). After a review of their titles and abstracts, some articles were discarded, since the anti-leishmanial activity (IC50) values were higher than 100 µg/mL (134), and they tested extract/natural compounds obtained through other natural sources (algae, fungi, etc.) (11). The full texts of the remaining articles were reviewed in detail. However, further articles were discarded after the full text had been reviewed (18) since they did not address much of the required information. Finally, 61 articles were evaluated as valuable to reach the goals of this review. The methodological validity of all 61 studies was proven prior to inclusion in the review by undertaking a critical appraisal using a standardized instrument [75].

3.4. Data Extraction and Analysis

The data extraction protocol included the scientific and family names, parts of the plant used, most active extract/ essential oil employed in the experiment, name of natural compound, Leishmania species and form, IC50 values, potential groups/compounds responsible for activity, clinical form of leishmaniasis, route, the dose of administration and scheme of treatment, the efficacy of the treatments in the experiment, cytotoxic activity, selectivity index, the authors, and year of publication. In the results analysis, an active extract/compound was considered if the IC50 value was less than or equal to 10 µg/mL against the promastigote or amastigote forms. Moderate activity was defined if the IC50 was greater than 10 and less than 50 µg/mL and weakly active if the IC50 value was greater than 50 µg/mL and less than 100 µg/mL.

4. Conclusions and Perspectives

Leishmaniasis threatens about 350 million people around the world and continues to represent a menace on a global scale. Without a doubt, it requires utmost attention due to the lack of vaccines for the prevention and reported resistance against available chemical drugs for treatment. The intolerably high incidence of millions of new cases of leishmaniasis per year worldwide and deficiencies in current treatment point to an urgent need for new medications.

As a means to facilitate the accessibility of information, this review updates and summarizes recent results on medicinal plants and natural compounds against different Leishmania species. The plants presented here have demonstrated a diverse range of activities against different forms of leishmaniasis with some showing high activities that could be reasonable starting points for the further development of effective and affordable novel drugs.

However, it was also evident that the majority of experiments were performed with the promastigote form. We believe that these studies are undoubtedly important because promastigotes are infectious to man and other animals. However, it is urgent that future studies should be conducted to find compounds with anti-amastigote activity too, since the morbimortality associated with Leishmania is caused by this form.

It Is pleasing that more and more investigations report on the anti-Leishmania activity in vivo and more studies are needed in this respect, increasing the number of potential candidate compounds for further drug development. In vitro studies are valuable for the screening of extracts and isolated compounds as well as for investigations of the cellular and molecular modes of action. Since many natural compounds are rapidly metabolized in the human body by liver enzymes and gastrointestinal microflora, animal experiments are indispensable to identify candidates with sufficient half-life times in vivo and anti-Leishmania activities in concentration ranges that are reachable in the human blood. However, in the literature inspected by us, only four plants and two natural compounds have been investigated both in vitro and in vivo, i.e., Prosopis juliflora [34], Ziziphus spina-christi [37], Piper pseudoarboreum [33], and Croton caudatus [76] as well as epigallocatechin 3-O-gallate [58] and apigenin [65], respectively. More investigations are required to allow a direct comparison of in vitro and in vivo data.

Further down this line of argumentation, standardized extracts and/or isolated phytochemicals need to be tested in randomized clinical trials. Without convincing clinical evidence on safety and efficacy, preparations from traditional medicine will hardly reach considerable recognition in the medical world.

Author Contributions

A.H.A.: wrote the manuscript draft; H.E.K.: manuscript editing, supervision of A.A.H.; A.H.A., M.M.M., W.J.O.: literature collection, manuscript editing; T.E.: supervised whole project and wrote, edited, and corrected the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare that there is no conflict of interest.

Funding Statement

This research received no external funding.

Footnotes

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

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