Download PDF

The Search for Putative Hits in Combating Leishmaniasis: The Contributions of Natural Products Over the Last Decade

Received date: 11 February 2021; Accepted: 7 May 2021; Published online: 14 July 2021

Abstract

Despite advancements in the areas of omics and chemoinformatics, potent novel biotherapeutic molecules with new modes of actions are needed for leishmaniasis. The socioeconomic burden of leishmaniasis remains alarming in endemic regions. Currently, reports from existing endemic areas such as Nepal, Iran, Brazil, India, Sudan and Afghanistan, as well as newly affected countries such as Peru, Bolivia and Somalia indicate concerns of chemoresistance to the classical antimonial treatment. As a result, effective antileishmanial agents which are safe and affordable are urgently needed. Natural products from both flora and fauna have contributed immensely to chemotherapeutics and serve as vital sources of new chemical agents. This review focuses on a systematic cross-sectional view of all characterized anti-leishmanial compounds from natural sources over the last decade. Furthermore, IC50/EC50, cytotoxicity and suggested mechanisms of action of some of these natural products are provided. The natural product classification includes alkaloids, terpenes, terpenoids, and phenolics. The plethora of reported mechanisms involve calcium channel inhibition, immunomodulation and apoptosis. Making available enriched data pertaining to bioactivity and mechanisms of natural products complement current efforts geared towards unraveling potent leishmanicides of therapeutic relevance.

Graphical Abstract

Keywords

Chemotherapeutics    Chemoinformatics    Natural products    Cytotoxicity    Leishmaniasis    Phenotypic screening    
Download fulltext PDF

1 Introduction

The debilitating rate of parasitic infections in the tropical and subtropical regions of developing countries has become alarming [1]. Vector-borne neglected tropical diseases and related synergetic co-infections, particularly leishmaniasis are very challenging and sophisticated to treat [2]. This is partly due to the existence of diverse parasitic species with different bionomics and sophisticated overlap between virulent factors. Activated immune response during disease exacerbation coupled with emerging resistance by both parasites and vectors against various treatment regimens have also contributed to this challenge [2, 3].

Leishmania, the etiological agent of leishmaniasis, is transmitted globally by over 90 different female sand-fly species of the Phlebotomus family, spread across 98 countries and four continents, with annual estimates of 1 million new cases and 30, 000 deaths as at 2017 [2, 4]. The exact disease burden is unknown, but statistics indicate that over 350 million people are at risk, signifying a prominent public health risk [2, 5, 6].

Leishmaniasis is curable if the disease is diagnosed early and the appropriate medication is administered. Typically, leishmaniasis is initially marked by dermotropic ulcers, which then progress into the visceral tissues, resulting in a late and more debilitating condition that can often lead to death if left untreated. In some cases, the destruction of the mucocutaneous membrane especially the nose, throat, and mouth have also been very common [2]. The degree of clinical outcome and its corresponding immunopathology depends primarily on the type of causative species, age of host, and the balance between the host immune response and how the parasites subvert these defense mechanisms. In cases where the victim's immune system is strong, Leishmania pathogens behave as opportunists by remaining dormant until the host's immunity is compromised. Additionally, when the host is immunosuppressed, relapses are usually prevalent resulting in treatment failures.

Some challenges associated with the management of leishmaniasis include systemic toxicity of administrated drugs, high cost of existing therapeutic options, lengthy treatment periods and drug resistance. Furthermore, confounding factors such as parasite diversity has hampered various intervention strategies and halted global efforts, necessitating an immediate search for new drug leads for development as the next generation of antileishmanial agents [7-9]. In lieu of this, the review seeks to bring to the fore the various classes of natural products recently discovered with antileishmanial potentials over the last decade. Even though, the review primarily reported compounds with potent bioactivity, few with low potency were reported since these could be optimized or their scaffolds may serve as skeletons for the development of future leishmanicides.

1.1 Trends in leishmanial chemotherapy and current panorama

Protection against leishmaniasis started with mimicking natural immunity through live inoculations [10] until modernized techniques including killed promastigotes and knocked out parasites came into play. Unfortunately, the presence of persistent lesions and the difficulty in estimating their efficacy rendered these approaches less effective [10, 11]. Efforts to alleviate leishmaniasis via chemotherapy include the use of pentavalent antimonial, which was essentially a small tartrate complex of antimony first reported in 1925 by Brahmachari [12, 13]. Although, antimoniate (SbⅤ) is still active after reduction by arsenate reductase to SbⅢ, Leishmania parasites are also susceptible to SbⅤ via oxidative stress.

Gene amplification studies involving the Adenosine Triphosphate (ATP) binding cassette transporters including the multi-resistance proteins that act as efflux pumps have been shown to contribute to antimony resistance in clinical isolates [14, 15]. Likewise, deletions of aquaporin membrane carrier genes and phenotypic changes of the parasite with subsequent induced effects on the microbicide activity and the efflux rate of antimony reaching the macrophages also contribute to the resistance [16].

In the mid-1960's pentamidine became the second choice to antimony resistant strains [17]. However, its utility like the antimonial was hampered due to severe vasomotor side effects and complex interactions with the pancreas which leads to the destruction of β-cells causing diabetes mellitus [17].

In the quest to expedite the time it takes for drugs to reach the market, strategies such as deciphering the cellular similarities between disease causing pathogens from phenotypic screening were developed. In the early 1960s, the anti-fungal amphotericin B from Streptomyces nodosus was used for treating leishmaniasis [18, 19]. This choice was widely accepted in most endemic areas due to its efficacy but not so in other areas especially East Africa (L. donovani) and South America (L. infantum) [20].

The anticancer agent alkyl phosphocholine (miltefosine) was the first oral formulation with strong protection against visceral leishmaniasis. Miltefosine works by modulating an apoptosis process induced by mitochondria membrane depolarization and phospholipid biosynthesis inhibition [21]. The main drawback in administering miltefosine for leishmaniasis treatment includes longer elimination time, lengthy treatment course, and miscarriage in pregnant patients after use [22].

A new and simple formulation of an old antibiotic paromomycin which inhibited translation with different modes of application (enteral, parenteral and topical) was also repurposed for leishmaniasis in 1967 [23, 24]. Unlike the other treatment options, paromomycin's toxic effects are very minimal, but its efficacy is quite poor. New optimum carriers targeting pathogen macrophage using albumin has recently been reported to increase efficiency [25].

Following the failure of miltefosine, a collaboration between the Walter Reed Army Institute of Research (WRAIR, USA) and GlaxoSmithKline (UK) identified sitamaquine as a promising alternative, but its apparent loss of efficacy in tegumentary leishmaniasis limited its use [26]. Subsequently, findings from amphotericin B use and its high curative rate in patients influenced another repurposing strategy using the oral anti-fungal azoles (fluconazole, itraconazole, and ketoconazole) as suitable control and cost-effective therapy [27, 28].

Due to the therapeutic challenges, new chemotypes with high potency in tandem with immunostimulatory activity targeting new proteins applicable to both visceral and cutaneous leishmaniasis cases are desperately needed.

1.2 Natural products as possible sources of new drugs against leishmaniasis

The lack of effective vaccines for control and concerted elimination campaign [2], and recent snail paced progress on leishmanial vaccine development does not guarantee any optimism. With the advancements in synthetic organic chemistry, combinatorial chemistry, and computational de novo drug discovery strategies, as well as high throughput screening techniques, only a few synthetically constructed drugs have been useful in combating leishmaniasis. Even with this, few natural product scaffolds represent major pharmacophores responsible for their curative effects. Between 2005 and 2010, about 19 natural products were registered for treatment of infectious diseases [29]. Similarly, over 69% of new small molecules used for the treatment of infectious diseases originated from natural products [30, 31].

Despite the large molecular weights of natural products which renders some of them less druglike, structural diversity, large chemical space and safety are characteristics that overrides synthetic alternatives. Treatments using extracts from plant families from endemic regions include Fabaceae [32], Annonaceae, Euphorbiaceae [31, 33, 34], Rutaceae [35-37], Myrsinaceae [31, 38], Liliaceae [39], Araliaceae [38], Simaroubaceae [40], as well as endophytes genera Alternaria [41], Arthrinium, Penicillium, Cochloibus, Fusarium, Colletotrichum, and Gibberella [42]. Additionally, the exploration of marine natural products has led to the identification of interesting natural products with diverse biomolecular functions [43, 44].

Despite the large molecular weights of natural products which renders some of them less druglike, structural diversity, large chemical space and safety are characteristics that overrides synthetic alternatives. Treatments using extracts from plant families from endemic regions include Fabaceae [32], Annonaceae, Euphorbiaceae [31, 33, 34], Rutaceae [35-37], Myrsinaceae [31, 38], Liliaceae [39], Araliaceae [38], Simaroubaceae [40], as well as endophytes genera Alternaria [41], Arthrinium, Penicillium, Cochloibus, Fusarium, Colletotrichum, and Gibberella [42]. Additionally, the exploration of marine natural products has led to the identification of interesting natural products with diverse biomolecular functions [43, 44].

Since the mid-eighties when the search for anti-leishmanial natural products became prominent, numerous metabolites originating from plants to current antileishmanial therapies have been reported. Lately, credible chemical entities from marine sources and endophytic species have also been reviewed [45-51]. This review presents the various classes of natural products from both flora and fauna that have been isolated over the last decade with anti-leishmanial properties. Also, the IC50/EC50 values and suggested mechanisms of action of these natural products are discussed.

1.3 Classification of natural products with anti-leishmania properties

1.3.1 Alkaloids

Among the characterized bioactive constituents from nature, alkaloids have provided a broad-spectrum activity against different ailments and demonstrated their suitability as potential drug leads. Phenotypic alterations in ultrastructure form of the infective cells and immunomodulatory investigation studies of isolated alkaloids within the last decade reveal 27 alkaloids (Table 1) with varying efficacies from strong to weak activity. The natural product 3 isolated from Cissampelos sympodialis acts as a calcium channel inhibitor with immunomodulatory effects through the enhancement of nitric oxide (NO) production in macrophages [52]. Studies of 4 from Croton pullei reported significant alterations in organelle membranes of the endoplasmic reticulum, kinoplast and golgi body, depicting an apoptosis-like process [53]. Treatment with spectaline alkaloids, 16 and 17 from dichloromethane fractions of the flower Senna spectabilis of Leishmania promastigotes also portray a similar molecular mechanism like its structurally related piperine amide alkaloid, which either modulates the sterol biosynthetic pathway or acts as an inhibitor of cell proliferation by mitochondrion organelle destruction [54]. Although, the exact mode of action has not been fully elucidated, 21 from Berberine vulgaris like the active alkaloid in Berberine aristate perpetuates a similar activity through respiration incapacitation and apoptosis [55]. However, 21 was identified as a potential cell membrane disruptor via sterol biosynthesis inhibition [56], while 22 induces reactive oxygen species (ROS) generation. Structural activity relation (SAR) studies of high affinity protein kinase inhibitors, staurosporine-based compounds (24-27) revealed the 4th C methyl amine and 7th C hydrogen acceptor as the cause for the reinforced activity observed in L. donovani, which had major morphological changes in the flagella pocket and plasma membrane because of signal blockage via phosphokinase (PK) inhibition.

Table 1

23 alkaloids isolated from various flora and fauna together with their IC50 and toxicity tested on some Leishmania species

Natural product source Chemical structure Class of natural product IC50/μg/mL Organism tested Toxicology References
Paenibaccillus sp.
(Marine)		 Imidazole 28.1 L. donovani
(Promastigote)		 Low toxicity profiles to mouse macrophages RAW 264.7 cell lines.>250 µM [57]
Paenibaccillus sp.
(Marine)		 Imidazole 0.203 L. major
(Promastigote)		 MIC=25 μM [58]
1.90 L. donovani
(Promastigote)
Cissampelos sympodialis Isoquinoline 80.0 L. chasi
(Promastigote)		 IC50=0.056 μM against human laryngeal cancer cells (HEP-2cells) and 0.067 μM against human mucoepide cells (NCIH-292) [52]
Croton pullei var. glabrior Piperidine 6.27 L. amazonensis
(Amastigote)		 Nontoxic as against murine macrophages after treatment with 79 µM of julocrotine [53]
Aconitum spicatum Pyrrolidine 56.0 L. major No toxicity against MCF7, HeLa, PC3 cancer cell lines and 3T3 normal fibroblast cell line at 30 µM [59]
36.1
Helietta apiculata Quinoline 17.3 L. donovani [60]
Quinoline 25.5
Thalictrum alpinum Isoquinoline 0.175 L. donovani [61]
0.639
6.60
Trichosprum sp. Piperazine 96.3 L. donovani [62]
Piperazine 82.5 L. donovani
Piper choba Amide 16.0 L. donovani
(Promastigotes)		 CC50 = 0.76 μM and 0.83 μM against brine shrimp cells [63]
Amide 30.0
Senna spectabilis Piperidine 24.9 L. major
(Promastigotes)		 No observed lethality against J774 murine macrophage [54]
Aspidosperma ramiflorum Indole 18.5 L. amazonensis
(Promastigotes)		 [64]
12.6
Beilschmiedia alloiophylla quinoline 2.95 [65]
Berberis vulgaris Isoquinoline 2.10
2.90		 L. major
L. tropica
(Promastigotes)		 Observed toxicity against murine macrophage was at 9.18 μM [66]
Piper longum Amide 9.12 L. donovani
(promastigotes)		 Test against J774A.1 cell line indicated a high cytotoxicity at 5.05±0.64 μg/mL.
393		 [67]
2.81 L. donovani
(amastigotes)
Spongia sp. and Ircinia sp.
(Marine)		 Indole 9.6 Toxicity profile against mammalian L6 cells was [68]
Streptomyces sanyensis
(Marine)		 Indolocarbazole 0.0075 L. amanzonensis
(promastigotes)		 The series showed low selectivity against murine macrophage J774A.1 with CC50 of 5.20 [69]
0.0012 L. donovani
(promastigotes)
0.0002 L. amanzonensis
(amastigotes)
Indolocarbazole 0.00017 L. amanzonensis
(promastigotes)		 8.74
0.0045 L. donovani
(promastigotes)
0.0224 L. amanzonensis
(amastigotes)
Indolocarbazole 0.037 L. amanzonensis
(promastigotes)		 > 40
>0.089 L. donovani
(promastigotes)
0.005 L. amanzonensis
(amastigotes)
Indolocarbazole 0.0224 L. amanzonensis
(promastigotes)		 > 40
>0.089 L. donovani
(promastigotes)

1.3.2 Phenolics

As characterized by hydroxy-phenyl groups, polyphenolics are widely distributed in nature and have been isolated from different plants. In traditional medicine phenolics have received much interest in phyto-therapeutics for the treatment of ailments ranging from non-infectious to infectious diseases. These chemotypes include compounds like coumarins, flavonoids, quinones, lignans, flavone glycosides amongst others (Table 2). Flavonoids from Selaginella sellowi when tested against different forms of Leishmania revealed a pro-drug mechanism for 28 but an activated NO generation for 29 [70]. The difference in the mode of action of these two flavonoids may be due to their conformational orientations. Similar investigations to understand the possible cause of apoptosis induced by 30 and 31 suggested a mitochondrial dysfunction with no influence on ROS [71]. However, evidence from suicidal action of some quercetin analogues have also indicated iron chelation, arginase inhibition, and topoisomerase Ⅱ intercalation as possible mechanisms [72]. From the same Nectandra genus, inhibitory activity of 34 and 43 have been fully elucidated. Results indicated an inactivation of exacerbatory immunogens with reduced calcium levels and depolarized mitochondria potential [73]. Studies with similar compounds against melanoma cells indicated an apoptosis process confirming the depolarization activity [74]. Deciphering the exact mechanism underpinning the leishmanicidal action of isolated compounds from Connarus seberosus, it was revealed that defects in the mitochondria and plasma membrane structure with the evidence of lipid accumulation were caused by 55 and 56 [75]. Comparing 58 and its 3-O-methyl analog, 59, to rosmarinic acid (based on the shared catechol nucleus), their potential mode of action is suggested as inhibition of reactive oxygen species [76, 77]. 75 as a chemo-preventive agent acts by reducing inflammatory symptoms by suppressing NF-κB expression and other pro-inflammatory factors including iNOS, COX-2, TNF-α, IL-1β, and IL-6 [78]. Compound 74 emulates an apoptosis induced suicidal mechanism which involves DNA fragmentation, inhibition of inflammation cytokines and the activation of caspases with downstream effects on gene transcriptional process [79]. Structural similarities of anti-inflammatory coumarins with 74 precludes a similar mechanism of action [80]. From the isolates of Arrabidaea brachypoda only 67 altered organelle structure and function by attenuating cytoplasm puncturing and golgi apparatus swellings [81].

Table 2

Various classes of phenolic compounds with their IC50 exhibiting antileishmanial properties

Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Selaginella sellowi Flavonoid 0.10 L. amazonensis IC50=5.57 and 4.09 µM against Murine macrophages (J774.A1) and fibroblast cells (NIH/3T3) [70]
Flavonoid 2.80 CC50=5.75 and 47.4 µM against murine macrophage (J774.A1) and fibroblast cells (NIH/3T3).
Strychnos pseudoquina Flavonoid 11.9
2.02		 L. infantum
L. amazonensis		 Low-toxicity to infected murine macrophage up to 125 μM and low hemolytic activity in red blood cells [71]
Flavonoid 2.56 L. amazonensis No significant toxicity  >  199 μM
Lendenfeldia. dendyi and Sinularia dura
(Marine)		 Phenyl ether 18.0 L. donovani
(Promastigotes)		 Low toxicity profile to VERO cells, pig kidney epithelia, human dermal carcinoma oral [82]
Phenyl ether 13.6 L. donovani Ductile carcinoma breast, human malignant melanoma up to 13 µM
Nectandra leucantha Phenyl ether 8.70
6.00
34.9		 L. donovani
(Intra Amastigotes)		 Nontoxic to mammalian peritoneal macrophages up to
> 293.8 μM
112.1 μM
> 292.1 μM		 [83]
Alpinia galanga Monolignols 10.5
16.6		 L. donovani
(Promastigotes)		 [84]
Phenol ester 8.80
5.60
Hellieta apiculata Coumarin 35.8
27.5
32.1		 L. amazonensis
L. infantum
L. brazilensis		 [60]
Coumarin 18.5
27.4
21.5		 L. amazonensis
L. infantum
L. brazilensis
Nectandra oppositifolia Butanolide 3.58 Nontoxic against NCTC cell up to 42.3 µM [85]
Piper regnellii var. pallescens Lignan 5.00 L. amazonensis [86]
Nectandra cuspidata Flavonoid 38.5 L. amazonensis
(Amastigotes)		 Low cytotoxicity in J774.A1 macrophages [87]
Flavanoid 71.3
Flavanoid 34.0
Plumbago zeylanica Quinone 1.05
(EC50)		 L. donovani
(Amastigotes)		 Very toxic to on RAW 264.7 macrophage cell lines [88]
Ocimum gratissimum Monolignol 0.81 L. infantum Nontoxic in murine macrophages RAW 264.7 cells lines 29.0 µM [89-91]
Monolignol 18.5 >100 µM
Monolignol 14.9 97.7 µM
Vernonia polyanthes Quinone 50.5 L. amazonensis
(Promastigotes)		 At conc.>52.4 µM in infected murine macrophages [92]
Quinone 10.2 At conc.>37.23 µM in infected murine macrophages
Connarus Suberosus Chromanone 1.13
4.5
5.2		 L.amazonensis
(amastigotes)
L. amazonensis
(promastigotes)
L.infantum (promastigotes)		 Toxic at 18.3 µM against murine macrophages. [75]
Lignan 11.4
15.5
7.1		 L. amazonensis
(promastigotes)
L.infantum (promastigotes)
L. amazonensis
(promastigotes		 Reduction cell viability was at 116 µM.
Piper aduncum Lignan 0.31
0.28		 L. amazonensis
(promastigotes)
L. braziliensis
(promastigotes)		 Critical changes in the morphology of 3T3 fibroblast cell lines and its viability was observed at 25 µM and above. [93]
Hyptis pectinata Flavonoid 2.5 L. braziliensis
(promastigotes)		 N.T [76]
Flavonoid >36.0
Geosmithia langdonii Phenyl propene 0.05 L. donovani
(promastigotes)		 N.T [94]
Geosmithia langdonii Carbasugar
Carbasugar		 0.34
0.20		 L. donovani
(promastigotes)		 N.T [95]
Ferula narthex Coumarin 43.77 L. amanzonensis
(promastigotes)		 N.T [96]
Coumarin 46.81
Coumarin 11.51
Coumarin 46.77
Arrabidaea brachypoda Flavonoid 0.004
0.017
0.013
0.024		 L. amanzonensis
(amastigotes)
L. amanzonensis
(promastigotes)
L. brazilensis
(promastigotes)
L. infantum
(promastigotes)		 High lethality against macrophages at concentration above 20 μM [81]
Flavonoid 0.02
0.017
0.037
0.012		 L. amanzonensis
(amastigotes)
L. amanzonensis
(promastigotes)
L. brazilensis
(promastigotes)
L. infantum
(promastigotes)
Trixis antimenorrhoea Flavonoid 78
96		 L. amazonensis
(promastigote)
L. brazilensis
(promastigote)		 N. T [97]
Flavonoid 19
5.8
Anogeissus leiocarpus Flavonoid 0.003 L. donovani
(promastigotes)		 CC50>100 µg/ml [98]
Sassafras albidum Lignan 15.8 L. amazonensis
(Promastigote)		 Nontoxic against BALB/c mouse macrophages up to
282		 [36]
Lignan 45.4 190
Zanthoxylum tingoassuiba Coumarin 57.7 L. amazonensis
(Promastigote)		 N. T [99]
Coumarin 70.0
Lignan 12.0

1.3.3 Terpenes and terpenoids

Another group of secondary metabolites with interesting anti-parasitic activities are terpenes. Ultrastructural changes of 79 in phenotypic screenings indicated mitochondrial blebs and lipid deformities [100, 101]. 80 isolated from essential oils of Tetradenia riparia were found to distort promastigote structure especially the fate of its chromatin followed by an apoptosis process which is suspected to be caused by caspase activation [102, 103] (Tables 3 and 4).

Table 3

Various classes of terpenes and terpenoids with their IC50 exhibiting antileishmanial properties

Natural product source Chemical structure Class of natural product IC50/μg/mL Organism tested Toxicology References
Parinari excelsa Triterpenoid 0.05 L. donovani
(amastigotes)		 Cell viability assay with L6 cell lines revealed the lethal concentration at 73.5 μg/mL [120]
Morinda lucida Monoterpenoid 1.17 L. donovani
(promastigotes)		 [121]
Canistrocarpus cervicornis
(Marine)		 Diterpene 4.00 L. amazonensis
(Intra Amastigotes)		 Non-toxic up to 515 µM in human macrophage strains J774G8 [100]
Tetradenia riparia Sesquiterpene 2.45 L. amazonensis
(Promastigotes)		 high toxicity against mouse peritoneal macrophages = 1.69 µM [122]
Laurencia dendroidea
(Marine)		 Sesquiterpene 10.8 L. amazonensis
(Intra Amastigotes)		 CC50 in macrophages and lymph nodes in amastigotes cervical BALB/c mice
160.2 and 172.8 µM		 [123]
Sesquiterpene 1.50 112.9 and 120.2 µM
Sesquiterpen 1.62 133.5 and 139.3 µM
Combretum leprotum Triterpene 3.30 L. amazonensis
(Promastigotes)		 Non-toxic against mouse peritoneal macrophages [124]
Triterpene 3.48
Triterpene 5.80
Vanillosmopsis arborea Sesquiterpene 10.7 L. amazonensis
(Amastigotes)		 Low cytotoxicity to macrophage J774.G8 cell lines 451 µM [106]
Croton cajucara Diterpene 20.0 L. amazonensis
(Axenic Amastigotes)		 [108]
Diterpene 41.4
Triterpene 58.3
Croton sylvaticus Diterpenoid 10.0 L. major(Promastigotes)
 Observed toxicity was low at 247.83 µM [125]
10.0 L. donovani
(Promastigotes)
Sterculia villosa Triterpenoid 15.0 L. donovani
(Intracellular Amastigotes)		 N.T [126]
Salvia deserta Diterpenoid 0.46 L. donovani N. T [35]
Diterpenoid 3.30
Diterpenoid 7.40
29.4
Garcinia achachairu Monoterpenoid 10.4 L. amazonensis N. T [127]
18.4 L. brazilensis
Rapanea ferruginea 24.1 L. amazonensis N. T [127]
6.10 L. brazilensis
Calea zacatechichi Sesquiterpene
Lactone		 1.89 L. donovani [116]
Sesquiterpene
Lactone		 0.771
Sesquiterpene
Lactone		 0.898
Sesquiterpene
Lactone		 1.74
Sesquiterpene
Lactone		 3.09
Sesquiterpene
Lactone		 1.60
Tanacetum parthenium Sesquiterpene
Lactone		 2.60 L. amazonensis
(promastigotes)		 Low toxicity towards J774G8 cells [128]
Plumeria bicolor Monoterpene
lactone		 0.409 L. donovani
(Amastigotes)		 CC50=20.6 µM [129]
Monoterpene
Lactone		 1.19 CC50=24 μM
Pseudelephantopus spicatus Sesquiterpene
lactone		 0.0794 L. amazonensis High selectivity towards parasites as compared to mammalian cells with
>100, >100 µM and>100 µM µM against Hela, L929 and B16F10 cell lines
58.5 µM, >100 µM and>100 µM against Hela, L929 and B16F10 cell lines
Toxic towards RAW264.7, HONE-1, KB and HT 29 cell lines with 15.6 µM, 8.8 µM, 8.2 µM and 4.7 µM respectively		 [130]
Sesquiterpene
lactone		 0.142
Triterpenoid 0.451
Calea pinnatifida Sesquiterpene
Lactone		 1.73 L. amazonensis
(Promastigotes)		 At 4.11 µM, toxic to J774 macrophages [115]
L. amazonensis
(Amastigotes)		 75.5 µM
Sesquiterpene
lactone		 4.24
Spongia sp. and Ircinia sp.
(Marine)		 Diterpene 0.75 L. donovani Toxicity profile against mammalian L6 cells was [68]
9.64
Sesterterpene 5.60 127
Sesterterpene 4.80 83.1
Sesterterpene 10.2 > 217
Triterpene 15.9 >146
Sesterterpene 14.2 >254
Tetraterpene 18.9 4.36
Baccharis tola Diterpenoid 4.60 L. brazilensis All compounds showed high cytotoxicity in human U937 macro phages with values lower than 347 μM [131]
Diterpenoids 5.30
Jatropha muitifida Diterpenoid 11.9 L. donovani Low toxicity profile against VERO cells [132]
Diterpenoid 4.69
Diterpenoid 4.56
Psidium Guajava Triterpene 1.01 L. infantum
(Axenic Amastigotes)		 At conc.=12.2 µM in mouse macrophage cell lines J774A.1 [133]
Triterpene 1.32 At conc.=20.8 µM against same cell lines
Cystoseira baccata
(Marine)		 Diterpenoids 20.4 L. infantum
(promastigotes)		 Non-toxic up to
126.6		 [134]
Diterpenoids 44.5 84.5
Pseudelephantopus spiralis Sesquiterpene
lactone		 0.06 L. infantum
(promastigotes)
L. infantum
(amastigotes)
L. infantum
(promastigotes)
L. infantum
(promastigotes)
L. infantum
(amastigotes)		 1.47±0.08
0.97±0.07
5.57±1.9		 [135]
Sesquiterpene
lactone		 0.012
0.02
0.005
Sesquiterpene
lactone		 0.244
0.048
Nectria pseudotrichia Sesquiterpene
Lactone		 0.092
0.023		 L. infantum
(promastigotes)
L. infantum
(amastigotes)		 3.17±1.0 [136]
Sesquiterpenoid 0.063 L. braziliensis
(amastigotes)		 Highly selective to parasites compared to VERO cells and THP-1 (a human leukaemia monocytic cell line). All>200 µM.
Monoterpene 0.104
Monoterpene 0.117
Monoterpene 0.37
Croton echioides Diterpenoid 0.11 L.amansonensis
(promastigotes)		 N.T [137]
Diterpenoid 0.027
Diterpenoid 0.025
Taxodium distichum Diterpenoid 2.5 L. donovani
(promastigotes)		 High toxicity against HT-29 colorectal carcinoma cells [138]
0.52 L. amazonensis
Lippia sidoides Monoterpene 23.9 L. amazonensis
(Promastigotes)		 36.5 µM
>100 µM
63.6 µM		 [139]
Monoterpene 11.0
Monoterpene 15.1
Trixis antimenorrhoea 0.3 L. amazonensis
(promastigote)		 N. T [97]
Sesquiterpene 0.96 L. brazilensis
(promastigote)
Bifurcaria bifurc-ata
(Marine)		 Diterpene 18.8 L.donovani Toxicity potential against L6 primary myoblast cell was observed at 56.6 µM [140]
Dictyota spiralis
(Marine)		 Diterpene 15.47 L. amazonensis
(promastigote)
L. amazonensis
(promastigote)		 23.4
69		 [141]
Diterpene 36.81
Stypopodium zonale
(Marine)		 Diterpene 9 L. amazonensis
(amastigotes)		 8.4 μM [142]
Plumarella delicatissima
(Marine)		 Diterpene 0.025 L. donovani
(amastigotes)		 Cytotoxicity potential against human lung carcinoma, cells exhibited low toxic potentials which were
>50
Diterpene 0.026 >50
Diterpene 0.034 >50
Diterpene 0.022 >50
Diterpene 1.9 >50
Diterpene 4.4 >50
Laurencia viridis
(Marine)		 Diterpene 8.36
28.26		 L. amazonensis (Promastigote)
L. donovani
(promastigotes)		 0.22 [143]
Diterpene 7.00
18		 L. amazonensis (Promastigote)
L. donovani
(promastigotes)		 4.6
Diterpene 34.65 0.6
Diterpene 12.96 1.4
Diterpene 10.32 >100
Dysidea avara
(Marine)		 Sesquiterpene 28.21 L. infantum
(Promastigotes)		 Low toxicity against human microvascular endothelial cells and (human acute monocytic leukemia cells with CC50 62.19 and>100 respectively. [144]
20.28 L. tropica
(Promastigotes)
7.64 L. infantum
(Amastigote)
Sesquiterpene 7.42 L. infantum
(Promastigotes)
 36.8
7.08 L. tropica
(Promastigotes)		 31.75
3.19 L. infantum
(Amastigote)

Table 4

Various classes of steroids, fatty alcohol, lignan, and butanolide with their IC50 exhibiting antileishmanial properties

Natural product source Chemical structure IC50 Organism tested Toxicity References
Sassafras albidum Steroid 54.3 L. amazonensis
(Promastigote)		 Nontoxic against BALB/c mouse macrophages up to
182		 [36]
Fatty alcohol 19.9 157
Trametes versicolor Steroid L. amazonensis
(Amastigote)		 Toxicity profile against peritoneal macrophages
 [152]
1.70 42.9 μM
Steroid 0.07 39.4 μM
Aspergillus terreus Steroid 11.2 L. donovani N. T [153]
Steroid 15.3
Steroid 54.3
Butenolide 7.27
Solanum sisymbriifolium Steroid 6.60 L. amazonensis N.T [127]
3.10 L. brazilensis
Steroid > 100 L. amazonensis N. T
59.8 L. brazilensis
Paecilomyces sp.
(Marine)		 18.2 L. amazonensis (Intra-Amastigote)
L. amazonensis		 Non-toxic up to 183 µM in mouse peritoneal macrophage. [154]
7.89
Musa paradisiaca Steroid 201 L. infantum
(Amastigote)		 Low toxicity profiles against mammalian raw cell lines
462 µM		 [155]
Steroid 185 569 µM
Steroid 127 1147 µM
Steroid 98.5 150 µM
Pentalinon andrieuxi 0.08 L. mexicana
(promastigotes)		 [150]
Steroid 0.009 L. mexicana
(amastigotes)
Steroid 0.03
0.004
Steroid 0.06
0.009
Porophyllum ruderale Terthiophene 37 L. amanzonensis
(amastigotes)		 CC50=370 μg/mL [151]
51 CC50=335 μg/mL
Marine Cyanobacteria
(Marine)		 Macrolide 4.67 µM L. donovani
(amastigotes)		 N.T [156]

Halogenated terpenes 72 and 83 from Laurencia dendroidea which only differ primarily in a double bond character also targets the same organelle via redox perturbation [104, 105]. The natural product 87 from Vanillosmopsis arborea show promising activity through apoptosis induction characterized by mitochondrial dysfunction and oxidative stress [106]. Similar mode of action was reported for 87 isolated from Tunisia chamomile essential oil against L. amazonensis and L. infantum [107]. Effects of clerodone terpenes, 88, 89 and 90 from the stem bark of Croton cajucara have been shown to obstruct ROS protection via trypanothione reductase inhibition [108].

Interest in marine natural products which led to the evaluation of marine terpenes like pentacyclic triterpene 92, which exhibited an anti-inflammatory action with enhanced levels of T cells and Th1 cytokines when compared to its control [109].

Elucidation of the exact mechanism of action of four triterpenes from the roots of Salvia deserta showed that despite the strong antioxidant capacity of 93, it also kill parasites by inhibiting isopentenyl diphosphate condensation with the major target being farnesyl diphosphate synthase [110]. Studies to also understand the molecular basics of 94 shows a similar action like 80, but fragmentation of DNA strands has been described for diterpene 95 and 96 [111, 112]. Inhibition of oxidative pathways particularly IFN-γ-related signaling by similar diterpenoid quinones isolated from the roots of Salvia officinalis has also been shown to prevent disease proliferation and further protecting the host specie [113]. Recent studies in estimating the role of the energy production in the form of ATP in Leishmania with acyl phloroglucinol derivatives has revealed 97 as a mitochondria complex Ⅱ/Ⅲ inhibitor [114].

Like terpenes which are formed by the head to tail condensation of isoprene units, terpenoids (terpenes with oxygen-containing functional group) also represent a unique group of natural products with high functionalization and promising pharmacological activity. Isolation of six germacranolides from the leaves and stems of the Calea species have shown promising activities against L. donovani and L. amazonensis [115, 116]. Among them morphological assessment studies with 100 and 111 indicated alterations in the nucleus and mitochondria describing an apoptosis like process through the mitosis motor downregulation pathway [115]. Due to the similar core structure shared with germacra-1(10), 11(13)-dien-12, 6-olide a similar mechanism is envisaged for its counterpart 104 by aiding in generating ROS complementing the elucidated apoptosis process. The natural product 106 shares same structural core therefore may possess similar mode of action in addition to the inhibition of thiol-antioxidant enzymes [117]. Interestingly, 106 and its iso-conformer have also been disclosed to induce a pro-inflammatory inhibition via the NF-KB pathway [118]. On the other hand, 110 and 125 have also exerted multi-spectral activities including suppression of cell proliferation modulators and upregulation of microbicidal NO species [119].

1.3.4 Steroids

Steroids are a class of natural or synthetic organic compounds with three six membered rings fused with a five membered ring. Ergosterol, the main sterol in Leishmania parasite constitute a major component of the cell membrane and mitochondrion of the parasite which when inhibited leads to parasite death. 164 extracted from Trametes versicolor mimics Leishmania ergosterol due to similarities in core structure but a break in oxygen–oxygen bond in ergosterol peroxide unleashes oxidation on lipids, proteins and nucleic acids of the parasite by free radical reaction leading to serious toxicity to the Leishmania parasite [145]. Apart from the biological formation of bridge peroxides, the deleterious effects of other lanostane type steroids on membrane state and integrity causing parasite death has been reported [146, 147]. Also, anti-infective studies of Sassafras albidum and its bioactivity guided fractionation reported a sterol and fatty alcohol, 162 and 163 respectively [36] as promising antileishmanial compounds. 162 which differs from cholesterol at C24 position is believed to kill the parasite via an apoptosis mechanism involving DNA fragmentation, inhibition of inflammation cytokines and the activation of caspases [148, 149]. Evaluating the suicidal action of active isolates from Pentalinon andrieuxii, 181 induced changes in immune responses particularly via necrosis and apoptosis characterized by increase in IL2 and IFN-γ which insinuates the control of pro-inflammatory cytokines by anti-inflammatory counterparts [150]. 182 halted the process of electron transport and ATP generation in the mitochondria [151]. In addition, plasma membrane alterations with the administration of the other isolates depicts a sterol metabolism inhibition as a contributing factor to parasite death [151].

2 Conclusion

Though humans and natural products did not co-evolve, chemical prototypes from natural origins have numerous targets in both human and animal diseases. Their structural diversity, large chemical space and safety are intriguing characteristics that makes them very attractive. Diverse biomolecular functions including anti-leishmanial potentials are possessed by various plant families including Fabaceae, Annonaceae, Euphorbiaceae, Rutaceae, Myrsinaceae, Liliaceae, Araliaceae and Simaroubaceae, as well as endophytes genera Alternaria, Arthrinium, Penicillium, Cochloibus, Fusarium, Colletotrichum, and Gibberella, and marine natural product possess.

Management of leishmaniasis is plagued with systemic toxicity, high cost of existing drugs, lengthy treatment periods, drug resistance and parasite diversity. Different classes of natural products such as alkaloids, terpenes, terpenoids, and phenolics are examples of compounds evaluated towards the treatment of leishmaniasis. They exert their antileishmanial activities through calcium channel inhibitors, immunomodulatory through the enhancement of NO in macrophages, alterations in organelle membranes of the endoplasmic reticulum, respiration incapacitation and apoptosis. Other antileishmanial related mechanisms include cell membrane disruption via sterol biosynthesis inhibition, reactive oxygen species (ROS) generation, iron chelation, arginase inhibition, topoisomerase Ⅱ intercalation, suppressing NF-κB expression and other pro-inflammatory, and trypanothione reductase inhibition.

Notes

Author contributions

POS, RKA and SKK initiated the work, POS wrote the first draft supervised by SKK and POS All the authors contributed to the writing of the review, read and accepted the final draft article.

Declarations

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    T.S. Tiuman, A.O. Santos, T. Ueda-Nakamura, B.P.D. Filho, C.V. Nakamura, Int. J. Infect. Dis. 15 (2011) PubMed Google Scholar
  2. 2.
  3. 3.
    B. Pérez-Cabezas, P. Cecílio, T.B. Gaspar, F. Gärtner, R. Vasconcellos, A. Cordeiro-da-Silva, Front. Cell. Infect. Microbiol. 9, 30 (2019) CrossRef PubMed Google Scholar
  4. 4.
  5. 5.
    I. Okwor, J. Uzonna, Am. J. Trop. Med. Hyg. 94, 489 (2016) CrossRef PubMed Google Scholar
  6. 6.
    R. Arenas, E. Torres-Guerrero, M. R. Quintanilla-Cedillo, J. Ruiz-Esmenjaud, F1000Research 6 (2017) PubMed Google Scholar
  7. 7.
    N. Tiwari, M. R. Gedda, V. K. Tiwari, S. P. Singh, R. K. Singh, Mini-Reviews Med. Chem. 18 (2018) PubMed Google Scholar
  8. 8.
    K. Jain, N.K. Jain, J. Immunol. Methods 422, 1 (2015) CrossRef PubMed Google Scholar
  9. 9.
    S. Emami, P. Tavangar, M. Keighobadi, Eur. J. Med. Chem. 135, 241 (2017) CrossRef PubMed Google Scholar
  10. 10.
    N. Dunning, S. Ali, Bioscience Horizons 2 (2009) PubMed Google Scholar
  11. 11.
    S. Srivastava, P. Shankar, J. Mishra, S. Singh, Parasites and Vectors 9 (2016) PubMed Google Scholar
  12. 12.
    P. L. Olliaro, P. J. Guerin, S. Gerstl, A. A. Haaskjold, J. A. Rottingen, S. Sundar, Lancet Infect. Dis. 5, 763 (2005) CrossRef PubMed Google Scholar
  13. 13.
    P.L. Olliaro, P.J. Guerin, S. Gerstl, A.A. Haaskjold, J.A. Rottingen, S. Sundar, Lancet Infect. Dis. 5, 763 (2005) CrossRef PubMed Google Scholar
  14. 14.
    J. N. Rugani, C. M. F. Gontijo, F. Frézard, R. P. Soares, R. L. Do Monte-Neto, Mem. Inst. Oswaldo Cruz 114 (2019) PubMed Google Scholar
  15. 15.
    F. Frézard, R. Monte-Neto, P.G. Reis, Biophys. Rev. 6, 119 (2014) CrossRef PubMed Google Scholar
  16. 16.
    G. Mandal, S. Mandal, M. Sharma, K.S. Charret, B. Papadopoulou, H. Bhattacharjee, R. Mukhopadhyay, PLoS Negl. Trop. Dis. 9 (2015) PubMed Google Scholar
  17. 17.
    S. Sundar, J. Chakravarty, Expert Opin. Pharmacother. 16, 237 (2015) CrossRef PubMed Google Scholar
  18. 18.
    A.C.O. Souza, A.C. Amaral, Front. Microbiol. 8, 336 (2017) PubMed Google Scholar
  19. 19.
    A.S. Nagle, S. Khare, A.B. Kumar, F. Supek, A. Buchynskyy, C.J.N. Mathison, N.K. Chennamaneni, N. Pendem, F.S. Buckner, M.H. Gelb, V. Molteni, Chem. Rev. 114, 11305 (2014) CrossRef PubMed Google Scholar
  20. 20.
    A. Tamiru, B. Tigabu, S. Yifru, E. Diro, A. Hailu, B.M.C. Infect, Dis. 16, 548 (2016) PubMed Google Scholar
  21. 21.
    J.R. Luque-Ortega, L. Rivas, Antimicrob. Agents Chemother. 51, 1327 (2007) CrossRef PubMed Google Scholar
  22. 22.
    J. Pijpers, M. L. Den Boer, D. R. Essink, PLoS Negl. Trop. Dis. 13, 1 (2019) PubMed Google Scholar
  23. 23.
    S. Sundar, J. Chakravarty, Expert Opin. Investig. Drugs 17, 787 (2008) CrossRef PubMed Google Scholar
  24. 24.
    V. Wiwanitkit, Ther. Clin. Risk Manag. 8, 323 (2012) PubMed Google Scholar
  25. 25.
    W. Khan, R. Kumar, S. Singh, S.K. Arora, N. Kumar, Drug Test. Anal. 5, 468 (2013) CrossRef PubMed Google Scholar
  26. 26.
    P.M. Loiseau, S. Cojean, J. Schrével, J. Parasite, La Société Fran-çaise Parasitol. 18, 115 (2011) PubMed Google Scholar
  27. 27.
    T.J. Gintjee, M.A. Donnelley, G.R. Thompson, Fungi 6, 28 (2020) CrossRef PubMed Google Scholar
  28. 28.
    S.T. De Macedo-Silva, J.A. Urbina, W. De Souza, J.C.F. Rodrigues, PLoS ONE 8 (2013) PubMed Google Scholar
  29. 29.
    B.B. Mishra, V.K. Tiwari, Eur. J. Med. Chem. 46, 4769 (2011) CrossRef PubMed Google Scholar
  30. 30.
    E. Patridge, P. Gareiss, M.S. Kinch, D. Hoyer, Drug Discov. Today 21, 204 (2016) CrossRef PubMed Google Scholar
  31. 31.
    I. V. Ogungbe, M. Singh, and W. N. Setzer, Antileishmanial Natural Products from Plants, 1st ed. (Elsevier B.V., 2012) PubMed Google Scholar
  32. 32.
    D.B. Santana, R.C. da Costa, R.M. Araújo, J.E. de Paula, E.R. Silveira, R. Braz-Filho, L.S. Espindola, Brazilian. J. Pharmacogn. 25, 401 (2015) CrossRef PubMed Google Scholar
  33. 33.
    C.V. Simoben, F. Ntie-Kang, S.H. Akone, W. Sippl, Nat. Products Bioprospect. 8, 151 (2018) CrossRef PubMed Google Scholar
  34. 34.
    N. Ullah, A. Nadhman, S. Siddiq, S. Mehwish, A. Islam, L. Jafri, M. Hamayun, Phyther. Res. 30, 1905 (2016) CrossRef PubMed Google Scholar
  35. 35.
    J. Búfalo, C.L. Cantrell, M.R. Jacob, K.K. Schrader, B.L. Tekwani, T.S. Kustova, A. Ali, C.S.F. Boaro, Planta Med. 82, 131 (2015) CrossRef PubMed Google Scholar
  36. 36.
    D. Pulivarthi, K.M. Steinberg, L. Monzote, A. Piñón, W.N. Setzer, Nat. Prod. Commun. 10, 1229 (2015) PubMed Google Scholar
  37. 37.
    L. Scotti, H. Ishiki, F.J.B. Mendonca, M.S. Silva, M.T. Scotti, Mini-Reviews. Med. Chem. 15, 253 (2015) CrossRef PubMed Google Scholar
  38. 38.
    R. Sen, M. Chatterjee, Phytomedicine 18, 1056 (2011) CrossRef PubMed Google Scholar
  39. 39.
    S.K. Venkatesan, P. Saudagar, A.K. Shukla, V.K. Dubey, Interdiscip. Sci. Comput Life Sci. 3, 217 (2011) CrossRef PubMed Google Scholar
  40. 40.
    R.S. Gabriel, A.C.F. Amaral, I.C. Lima, J.D. Cruz, A.R. Garcia, H.A.S. Souza, C.M. Adade, A.B. Vermelho, C.S. Alviano, D.S. Alviano, I.A. Rodrigues, Rev. Bras. Farmacogn. 29, 755 (2019) CrossRef PubMed Google Scholar
  41. 41.
    B.B. Cota, L.H. Rosa, R.B. Caligiorne, A.L.T. Rabello, T.M. AlmeidaAlves, C.A. Rosa, C.L. Zani, FEMS Microbiol. Lett. 285, 177 (2008) CrossRef PubMed Google Scholar
  42. 42.
    L.H. Rosa, V.N. Gonçalves, R.B. Caligiorne, T.M.A. Alves, A. Rabello, P.A. Sales, A.J. Romanha, M.E.G. Sobral, C.A. Rosa, C.L. Zani, Brazilian. J. Microbiol. 41, 420 (2010) CrossRef PubMed Google Scholar
  43. 43.
    D. Pech-Puch, M. Pérez-Povedano, O.A. Lenis-Rojas, J. Rodríguez, C. Jiménez, Mar. Drugs 18, 59 (2020) CrossRef PubMed Google Scholar
  44. 44.
    K. Hayibor, S. Kwain, E. Osei, A.P. Nartey, G.M. Tetevi, K.B.-A. Owusu, M. Camas, A.S. Camas, K. Kyeremeh, Int. J. Biol. Chem. Sci. 13, 1918 (2019) CrossRef PubMed Google Scholar
  45. 45.
    M. M. Basyoni, Parasitol. United J. 5 (2012) PubMed Google Scholar
  46. 46.
    R. M. de Oliveira, S. de A. Melo, T. A. da Penha-Silva, F. Almeida-Souza, and A. L. Abreu-Silva, in Leishmaniases as Re-Emerging Dis. (InTech, 2018) PubMed Google Scholar
  47. 47.
    L.R.T. Yamthe, R. Appiah-Opong, P.V.T. Fokou, N. Tsabang, F.F. Boyom, A.K. Nyarko, M.D. Wilson, Mar. Drugs 15, 323 (2017) CrossRef PubMed Google Scholar
  48. 48.
    I. A. Rodrigues, A. M. Mazotto, V. Cardoso, R. L. Alves, A. C. F. Amaral, J. R. D. A. Silva, A. S. Pinheiro, A. B. Vermelho, Mediators Inflamm. 2015 (2015) PubMed Google Scholar
  49. 49.
    R.M.K. Toghueo, Nat. Products Bioprospect. 9, 311 (2019) CrossRef PubMed Google Scholar
  50. 50.
    N. Fatima, S. Muhammad, A. Mumtaz, H. Tariq, I. Shahzadi, M. Said, M. Dawood, Br. J. Pharm. Res. 12, 1 (2016) PubMed Google Scholar
  51. 51.
    M. Oliveira, L. Barreira, K.N. Gangadhar, M.J. Rodrigues, T. Santos, J. Varela, L. Custódio, Phytochem. Rev. 15, 663 (2016) CrossRef PubMed Google Scholar
  52. 52.
    E. C. Da Silva, C. D. Rayol, P. L. Medeiros, R. C. B. Q. Figueiredo, M. R. Piuvezan, J. M. Brabosa-Filho, A. Fernandes Marinho, T. G. Silva, G. C. G. Militão, A. P. P. Cassilhas, P. P. De Andrade, Sci. World J. 2012 (2012) PubMed Google Scholar
  53. 53.
    L.R.C. Guimarães, A.P.D. Rodrigues, P.S.B. Marinho, A.H. Muller, G.M.S. Guilhon, L.S. Santos, J.L.M. Do Nascimento, E.O. Silva, Parasitol. Res. 107, 1075 (2010) CrossRef PubMed Google Scholar
  54. 54.
    S. M. M. Amyra Amat Sain, Azimah Amanah, Zuriati Zahari, Roshan Jahn Mohd Salim, Int. J. Pharmacol. Phytochem. Ethnomedicine 3, 1 (2016) CrossRef PubMed Google Scholar
  55. 55.
    N. Zhu, X. Cao, P. Hao, Y. Zhang, Y. Chen, J. Zhang, J. Li, C. Gao, L. Li, Cell Stress Chaperones 25, 417 (2020) CrossRef PubMed Google Scholar
  56. 56.
    N. Zorić, I. Kosalec, S. Tomić, I. Bobnjarić, M. Jug, T. Vlainić, J. Vlainić, B.M.C. Complement, Altern. Med. 17, 268 (2017) PubMed Google Scholar
  57. 57.
    G.M. Tetevi, S. Kwain, T. Mensah, A.S. Camas, M. Camas, A.K. Dofuor, F.A. Azerigyik, E. Oluwabusola, H. Deng, M. Jaspars, K. Kyeremeh, Molbank 2019, M1094 (2019) CrossRef PubMed Google Scholar
  58. 58.
    E. Osei, S. Kwain, G.T. Mawuli, A.K. Anang, K.B.A. Owusu, M. Camas, A.S. Camas, M. Ohashi, C.N. Alexandru-Crivac, H. Deng, M. Jaspars, K. Kyeremeh, Mar. Drugs 17, 9 (2019) PubMed Google Scholar
  59. 59.
    S.L. Shyaula, T. Tamang, N. Ghouri, A. Adhikari, S. Marasini, G.B. Bajracharya, M.D. Manandhar, M.I. Choudhary, Nat. Prod. Res. 30, 2590 (2016) CrossRef PubMed Google Scholar
  60. 60.
    M.E. Ferreira, A. Rojas de Arias, G. Yaluff, N.V. de Bilbao, H. Nakayama, S. Torres, A. Schinini, I. Guy, H. Heinzen, A. Fournet, Phytomedicine 17, 375 (2010) CrossRef PubMed Google Scholar
  61. 61.
    C.B. Naman, G. Gupta, S. Varikuti, H. Chai, R.W. Doskotch, A.R. Satoskar, A.D. Kinghorn, J. Nat. Prod. 78, 552 (2015) CrossRef PubMed Google Scholar
  62. 62.
    A. M. Metwaly, M. M. Ghoneim, and A. Musa, Two new antileishmanial diketopiperazine alkaloids from the endophytic fungus Trichosporum Sp (2015) PubMed Google Scholar
  63. 63.
    T. Naz, A. Mosaddik, M.M. Rahman, I. Muhammad, M.E. Haque, S.K. Cho, Nat. Prod. Res. 26, 979 (2012) CrossRef PubMed Google Scholar
  64. 64.
    A.D.C. Cunha, T.P.C. Chierrito, G.M.D.C. MacHado, L.L.P. Leon, C.C. Da Silva, J.C. Tanaka, L.M. De Souza, R.A.C. Gonalves, A.J.B. De Oliveira, Phytomedicine 19, 413 (2012) CrossRef PubMed Google Scholar
  65. 65.
    A. Mollataghi, E. Coudiere, A.H.A. Hadi, M.R. Mukhtar, K. Awang, M. Litaudon, A. Ata, Fitoterapia 83, 298 (2012) CrossRef PubMed Google Scholar
  66. 66.
    H. Mahmoudvand, S.A.A. Mousavi, A. Sepahvand, F. Sharififar, B. Ezatpour, F. Gorohi, E.S. Dezaki, S. Jahanbakhsh, ISRN Pharmacol. 2014, 1 (2014) PubMed Google Scholar
  67. 67.
    S. Ghosal, A. Deb, P. Mishra, R. Vishwakarma, Planta Med. 78, 906 (2012) CrossRef PubMed Google Scholar
  68. 68.
    I. Orhan, B. Şener, M. Kaiser, R. Brun, D. Tasdemir, Mar. Drugs 8, 47 (2010) CrossRef PubMed Google Scholar
  69. 69.
    L. Cartuche, I. Sifaoui, A. López-Arencibia, C.J. BethencourtEstrella, D.S. Nicolás-Hernández, J. Lorenzo-Morales, J.E. Piñero, A.R. Díaz-Marrero, J.J. Fernández, Biomolecules 10, 1 (2020) PubMed Google Scholar
  70. 70.
    Y.S. Rizk, A. Fischer, M.C. de Cunha, P.O. Rodrigues, M.C.S. Marques, M.F.C. de Matos, M.C.T. Kadri, C.A. Carollo, C.C.P. de Arruda, Mem. Inst. Oswaldo Cruz 109, 1050 (2014) CrossRef PubMed Google Scholar
  71. 71.
    P.S. Lage, M.A. Chávez-Fumagalli, J.T. Mesquita, L.M. Mata, S.O.A. Fernandes, V.N. Cardoso, M. Soto, C.A.P. Tavares, J.P.V. Leite, A.G. Tempone, E.A.F. Coelho, Parasitol. Res. 114, 4625 (2014) PubMed Google Scholar
  72. 72.
    F. Fonseca-Silva, J.D.F. Inacio, M.M. Canto-Cavalheiro, E.E. Almeida-Amaral, PLoS ONE 6 (2011) PubMed Google Scholar
  73. 73.
    S.S. Grecco, T.A. Costa-Silva, G. Jerz, F.S. de Sousa, G.A.A. Conserva, J.T. Mesquita, M.K. Galuppo, A.G. Tempone, B.J. Neves, C.H. Andrade, R.L.O.R. Cunha, M. Uemi, P. Sartorelli, J.H.G. Lago, Phytomedicine 24, 62 (2017) CrossRef PubMed Google Scholar
  74. 74.
    F.S. de Sousa, S.S. Grecco, N. Girola, R.A. Azevedo, C.R. Figueiredo, J.H.G. Lago, Phytochemistry 140, 108 (2017) CrossRef PubMed Google Scholar
  75. 75.
    L.S. Morais, R.G. Dusi, D.P. Demarque, R.L. Silva, L.C. Albernaz, S.N. Bao, C. Merten, L.M.R. Antinarelli, E.S. Coimbra, L.S. Espindola, PLoS ONE 15, 1 (2020) PubMed Google Scholar
  76. 76.
    R. A. Falcao, P. L. A. Do Nascimento, S. A.. De Souza, T. M. G. Da Silva, A. C. De Queiroz, C. B. B. Da Matta, M. S. A. Moreira, C. A. Camara, T. M. S. Silva, Evidence-Based Complement. Altern. Med. 2013 (2013) PubMed Google Scholar
  77. 77.
    M. Alagawany, M.E.A. El-Hack, M.R. Farag, M. Gopi, K. Karthik, Y.S. Malik, K. Dhama, Anim. Health. Res. Rev. 18, 167 (2017) CrossRef PubMed Google Scholar
  78. 78.
    V.K. Bajpai, M.B. Alam, K.T. Quan, M.K. Ju, R. Majumder, S. Shukla, Y.S. Huh, M.K. Na, S.H. Lee, Y.K. Han, Sci. Rep. 8, 9216 (2018) CrossRef PubMed Google Scholar
  79. 79.
    R.F. Espírito-Santo, C.S. Meira, R. DosSantosCosta, O.P.S. Filho, A.F. Evangelista, G.H.G. Trossini, G.M. Ferreira, E.S. Da Velozo, C.F. Villarreal, M.B.P. Soares, PLoS ONE 12, 0179174 (2017) PubMed Google Scholar
  80. 80.
    W. Gao, Q. Li, J. Chen, Z. Wang, C. Hua, Molecules 18, 15613 (2013) CrossRef PubMed Google Scholar
  81. 81.
    V. P. C. Rocha, C. Q. Da Rocha, E. F. Queiroz, L. Marcourt, W. Vilegas, G. B. Grimaldi, P. Furrer, E. Allémann, J. L. Wolfender, M. B. P. Soares, Molecules 24 (2019) PubMed Google Scholar
  82. 82.
    M.M. Radwan, A.S. Wanas, F.R. Fronczek, M.R. Jacob, S.A. Ross, Med. Chem. Res. 24, 3398 (2015) CrossRef PubMed Google Scholar
  83. 83.
    T.A. Da Costa-Silva, S.S. Grecco, F.S. De Sousa, J.H.G. Lago, E.G.A. Martins, C.A. Terrazas, S. Varikuti, K.L. Owens, S.M. Beverley, A.R. Satoskar, A.G. Tempone, J. Nat. Prod. 78, 653 (2015) CrossRef PubMed Google Scholar
  84. 84.
    A. Kaur, R. Singh, C.S. Dey, S.S. Sharma, K.K. Bhutan, I.P. Singh, Indian J. Exp. Biol. 48, 314 (2010) PubMed Google Scholar
  85. 85.
    T.A. Da Costa-Silva, G.A.A. Conserva, A.J. Galisteo, A.G. Tempone, J.H.G. Lago, J. Venom. Anim. Toxins Incl. Trop. Dis. 25, 1 (2019) PubMed Google Scholar
  86. 86.
    M.C. Vendrametto, A.O. dos Santos, C.V. Nakamura, B.P.D. Filho, D.A.G. Cortez, T. Ueda-Nakamura, Parasitol. Int. 59, 154 (2010) CrossRef PubMed Google Scholar
  87. 87.
    L.A.O. dos Ferreira, M.M. de Oliveira, F.L. Faleiro, D.B. Scariot, J.S. Boeing, J.V. Visentainer, M.B. Romagnolo, C.V. Nakamura, M.C.T. Truiti, Nat. Prod. Res. 32, 2825 (2018) CrossRef PubMed Google Scholar
  88. 88.
    B.B. Mishra, J.K. Gour, N. Kishore, R.K. Singh, V. Tripathi, V.K. Tiwari, Nat. Prod. Res. 27, 480 (2013) CrossRef PubMed Google Scholar
  89. 89.
    F.L. Dutra, M.M. Oliveira, R.S. Santos, W.S. Silva, D.S. Alviano, D.P. Vieira, A.H. Lopes, Acta Trop. 164, 69 (2016) CrossRef PubMed Google Scholar
  90. 90.
    S.M. de Morais, N.S. Vila-Nova, C.M.L. Bevilaqua, F.C. Rondon, C.H. Lobo, A.A.A.N. De Moura, A.D. Sales, A.P.R. Rodrigues, J.R. De Figuereido, C.C. Campello, M.E. Wilson, H.F. De Andrade, Bioorganic. Med. Chem. 22, 6250 (2014) CrossRef PubMed Google Scholar
  91. 91.
    T. Ueda-Nakamura, R.R. Mendonça-Filho, J.A. Morgado-Díaz, P.K. Maza, B.P.D. Filho, D.A.G. Cortez, D.S. Alviano, M.S.S. do Rosa, A.H.C.S. Lopes, C.S. Alviano, C.V. Nakamura, Parasitol. Int. 55, 99 (2006) CrossRef PubMed Google Scholar
  92. 92.
    A.M. do Nascimento, M.G. Soares, F.K.V.S. da Torchelsen, J.A.V. de Araujo, P.S. Lage, M.C. Duarte, P.H.R. Andrade, T.G. Ribeiro, E.A.F. Coelho, A.M. do Nascimento, World J. Microbiol. Biotechnol. 31, 1793 (2015) CrossRef PubMed Google Scholar
  93. 93.
    R. Parise-Filho, K.F.M. Pasqualoto, F.M.M. Magri, A.K. Ferreira, B.A.V.G. Da Silva, M.C.F.C.B. Damião, M.T. Tavares, R.A. Azevedo, A.V.V. Auada, M.C. Polli, C.A. Brandt, Arch. Pharm. (Weinheim). 345, 934 (2012) CrossRef PubMed Google Scholar
  94. 94.
    L.G. Malak, M.A. Ibrahim, D.W. Bishay, A.M. Abdel-Baky, A.M. Moharram, B. Tekwani, S.J. Cutler, S.A. Ross, J. Nat. Prod. 77, 1987 (2014) CrossRef PubMed Google Scholar
  95. 95.
    L.G. Malak, M.A. Ibrahim, A.M. Moharram, P. Pandey, B. Tekwani, R.J. Doerksen, D. Ferreira, S.A. Ross, J. Nat. Prod. 81, 2222 (2018) CrossRef PubMed Google Scholar
  96. 96.
    S. Bashir, M. Alam, A. Adhikari, R.L. Shrestha, S. Yousuf, B. Ahmad, S. Parveen, A. Aman, M.I. Choudhary, Phytochem. Lett. 9, 46 (2014) CrossRef PubMed Google Scholar
  97. 97.
    E.M. Maldonado, E. Salamanca, A. Giménez, G. Saavedra, O. Sterner, Phytochem. Lett. 10, 281 (2014) CrossRef PubMed Google Scholar
  98. 98.
    B. Attioua, L. Lagnika, D. Yeo, C. Antheaume, M. Kaiser, B. Weniger, A. Lobstein, C. Vonthron-Sénécheau, Int. J. Pharm. Sci. Rev. Res. 11, 1 (2011) PubMed Google Scholar
  99. 99.
    R.S. Costa, O.P.S. Filho, O.C.S.D. Júnior, J.J. Silva, M. LeHyaric, M.A.V. Santos, E.S. Velozo, Braz. J. Pharmacogn. 28, 551 (2018) CrossRef PubMed Google Scholar
  100. 100.
    A.O. dos Santos, E.A. Britta, E.M. Bianco, T. Ueda-Nakamura, B.P.D. Filho, R.C. Pereira, C.V. Nakamura, Mar. Drugs 9, 2369 (2011) CrossRef PubMed Google Scholar
  101. 101.
    A. Santos, E. Britta, T. Ueda-Nakamura, B. D. Filho, E. Bianco, V. Teixeira, R. Pereira, C. Nakamura, Planta Med. 75 (2009) PubMed Google Scholar
  102. 102.
    C. Garcia, C.O. Silva, C.M. Monteiro, M. Nicolai, A. Viana, J.M. Andrade, I. Barasoain, T. Stankovic, J. Quintana, I. Hernández, I. González, F. Estévez, A.M. Díaz-Lanza, C.P. Reis, C.A.M. Afonso, M. Pesic, P. Rijo, Future. Med. Chem. 10, 1177 (2018) CrossRef PubMed Google Scholar
  103. 103.
    P. Sitarek, M. Toma, E. Ntungwe, T. Kowalczyk, E. Skała, J. Wieczfinska, T. Śliwiński, P. Rijo, Biomolecules 10, 194 (2020) CrossRef PubMed Google Scholar
  104. 104.
    V.C. Desoti, D. Lazarin-Bidóia, D.B. Sudatti, R.C. Pereira, A. Alonso, T. Ueda-Nakamura, B.P.D. Filho, C.V. Nakamura, S.O. de Silva, Mar. Drugs(2012) (1631) PubMed Google Scholar
  105. 105.
    Y. Freile-Pelegrín, D. Tasdemir, Bot. Mar. 62, 211 (2019) CrossRef PubMed Google Scholar
  106. 106.
    A. V. Colares, F. Almeida-Souza, N. N. Taniwaki, C. D. S. F. Souza, J. G. M. Da Costa, K. D. S. Calabrese, A. L. AbreuSilva, Evidence-Based Complement. Altern. Med. 2013 (2013) PubMed Google Scholar
  107. 107.
    S. Hajaji, I. Sifaoui, A. López-Arencibia, M. Reyes-Batlle, I.A. Jiménez, I.L. Bazzocchi, B. Valladares, H. Akkari, J. LorenzoMorales, J.E. Piñero, Parasitol. Res. 117, 2855 (2018) CrossRef PubMed Google Scholar
  108. 108.
    G.S. Lima, D.B. Castro-Pinto, G.C. MacHado, M.A.M. Maciel, A. Echevarria, Phytomedicine 22, 1133 (2015) CrossRef PubMed Google Scholar
  109. 109.
    M. Saleem, Cancer Lett. 285, 109 (2009) CrossRef PubMed Google Scholar
  110. 110.
    Y.L. Liu, S. Lindert, W. Zhu, K. Wang, J.A. McCammon, E. Oldfield, Proc. Natl. Acad. Sci. USA 111, E2530 (2014) CrossRef PubMed Google Scholar
  111. 111.
    Y. Jia, C. Wu, B. Zhang, Y. Zhang, J. Li, Hum. Exp. Toxicol. 38, 227 (2019) CrossRef PubMed Google Scholar
  112. 112.
    K. Becker, S. Schwaiger, B. Waltenberger, D. Fuchs, C. K. Pezzei, H. Schennach, H. Stuppner, J. M. Gostner, Oxid. Med. Cell. Longev. (2018) PubMed Google Scholar
  113. 113.
    D. Slameňová, I. Mašterová, J. Lábaj, E. Horváthová, P. Kubala, J. Jakubíková, L. Wsólová, Basic Clin. Pharmacol. Toxicol. 94, 282 (2004) PubMed Google Scholar
  114. 114.
    L. Monzote, A. Lackova, K. Staniek, O. Cuesta-Rubio, L. Gille, Parasitology 142, 1239 (2015) CrossRef PubMed Google Scholar
  115. 115.
    L.A. Caldas, M.L. Yoshinaga, M.J.P. Ferreira, J.H.G. Lago, A.B. de Souza, M.D. Laurenti, L.F.D. Passero, P. Sartorelli, Bioorg. Chem. 83, 348 (2019) CrossRef PubMed Google Scholar
  116. 116.
    H. Wu, F.R. Fronczek, C.L. Burandt, J.K. Zjawiony, Planta Med. 77, 749 (2011) CrossRef PubMed Google Scholar
  117. 117.
    Y. Nakagawa, M. Iinuma, N. Matsuura, K. Yi, M. Naoi, T. Nakayama, Y. Nozawa, Y. Akao, J. Pharmacol. Sci. 97, 242 (2005) CrossRef PubMed Google Scholar
  118. 118.
    N. Fakhrudin, B. Waltenberger, M. Cabaravdic, A.G. Atanasov, C. Malainer, D. Schachner, E.H. Heiss, R. Liu, S.M. Noha, A.M. Grzywacz, J. Mihaly-Bison, E.M. Awad, D. Schuster, J.M. Breuss, J.M. Rollinger, V. Bochkov, H. Stuppner, V.M. Dirsch, Br. J. Pharmacol. 171, 1676 (2014) CrossRef PubMed Google Scholar
  119. 119.
    E.S. Yamamoto, B.L.S. Campos, J.A. Jesus, M.D. Laurenti, S.P. Ribeiro, E.G. Kallás, M. Rafael-Fernandes, G. Santos-Gomes, M.S. Silva, D.P. Sessa, J.H.G. Lago, D. Levy, L.F.D. Passero, PLoS ONE 10 (2015) PubMed Google Scholar
  120. 120.
    B. Attioua, D. Yeo, L. Lagnika, R. Harisolo, C. Antheaume, B. Weniger, M. Kaiser, A. Lobstein, C. Vonthron-Sénécheau, Pharm. Biol. 50, 801 (2012) CrossRef PubMed Google Scholar
  121. 121.
    F.A. Azerigyik, M. Amoa-Bosompem, T. Tetteh, F. Ayertey, A.N. Antwi, K.B.-A. Owusu, K.K. Dadzie, G.I. Djameh, M. TettehTsifoanya, S. Iwanaga, A.A. Appiah, T. Ohta, T. Uto, Y. Shoyama, N. Ohta, T.M. Gwira, M. Ohashi, European. J. Med. Plants 25, 1 (2018) PubMed Google Scholar
  122. 122.
    I.G. Demarchi, M.V. Thomazella, M.S. de Terron, L. Lopes, Z.C. Gazim, D.A.G. Cortez, L. Donatti, S.M.A. Aristides, T.G.V. Silveira, M.V.C. Lonardoni, Exp. Parasitol. 157, 128 (2015) CrossRef PubMed Google Scholar
  123. 123.
    F.L.S. Da MacHado, W. Pacienza-Lima, B. Rossi-Bergmann, L.M.S. De Gestinari, M.T. Fujii, J.C. Paula, S.S. Costa, N.P. Lopes, C.R. Kaiser, A.R. Soares, Planta Med. 77, 733 (2011) CrossRef PubMed Google Scholar
  124. 124.
    C.B.G. Teles, L.S. Moreira, A.D.A.E. Silva, V.A. Facundo, J.P. Zuliani, R.G. Stábeli, I. Silvm, J. Braz. Chem. Soc. 22, 936 (2011) CrossRef PubMed Google Scholar
  125. 125.
    J.A. Crentsil, L.R.T. Yamthe, B.Z. Anibea, E. Broni, S. K. Kwofie, J.K.A. Tetteh, D. Osei-Safo, Front. Pharmacol. 11 (2020) PubMed Google Scholar
  126. 126.
    A. Das, J.J. Jawed, M.C. Das, P. Sandhu, U.C. De, B. Dinda, Y. Akhter, S. Bhattacharjee, Int. J. Antimicrob. Agents 50, 512 (2017) CrossRef PubMed Google Scholar
  127. 127.
    V.C. Filho, C. Meyre-Silva, R. Niero, L.N. Bolda Mariano, F. Gomes Do Nascimento, I. Vicente Farias, V.F. Gazoni, B. Dos Santos Silva, A. Giménez, D. Gutierrez-Yapu, E. Salamanca, A. Malheiros, Evidence-Based Complement. Altern. Med. 2013 (2013) PubMed Google Scholar
  128. 128.
    B.P. da Silva, D.A. Cortez, T.Y. Violin, B.P.D. Filho, C.V. Nakamura, T. Ueda-Nakamura, I.C.P. Ferreira, Parasitol. Int. 59, 643 (2010) CrossRef PubMed Google Scholar
  129. 129.
    S. Singh, U. Sharma, P. Kumar, D. Singh, M. Dobhal, Indian J. Med. Res. 134, 709 (2011) CrossRef PubMed Google Scholar
  130. 130.
    G. Odonne, G. Herbette, V. Eparvier, G. Bourdy, R. Rojas, M. Sauvain, D. Stien, J. Ethnopharmacol. 137, 875 (2011) CrossRef PubMed Google Scholar
  131. 131.
    J.A. Murillo, J.F. Gil, Y.A. Upegui, A.M. Restrepo, S.M. Robledo, W. Quiñones, F. Echeverri, A.S. Martin, H.F. Olivo, G. Escobar, Bioorganic. Med. Chem. 27, 153 (2019) CrossRef PubMed Google Scholar
  132. 132.
    A. Falodun, V. Imieje, O. Erharuyi, A. Joy, P. Langer, M. Jacob, S. Khan, M. Abaldry, M. Hamann, Doc. Head. Asian Pac J Trop Biomed. 4, 374 (2014) CrossRef PubMed Google Scholar
  133. 133.
    C. Phakeovilay, S. Bourgeade-Delmas, P. Perio, A. Valentin, F. Chassagne, E. Deharo, K. Reybier, G. Marti, Molecules 24, 4536 (2019) CrossRef PubMed Google Scholar
  134. 134.
    C. Bruno de Sousa, K.N. Gangadhar, T.R. Morais, G.A.A. Conserva, C. Vizetto-Duarte, H. Pereira, M.D. Laurenti, L. Campino, D. Levy, M. Uemi, L. Barreira, L. Custódio, L.F.D. Passero, J.H.G. Lago, J. Varela, Exp. Parasitol. 174, 1 (2017) CrossRef PubMed Google Scholar
  135. 135.
    C. Girardi, N. Fabre, L. Paloque, A.P. Ramadani, F. Benoit-Vical, G. González-Aspajo, M. Haddad, E. Rengifo, V. Jullian, J. Ethnopharmacol. 170, 167 (2015) CrossRef PubMed Google Scholar
  136. 136.
    B.B. Cota, L.G. Tunes, D.N.B. Maia, J.P. Ramos, D.M. De Oliveira, M. Kohlhoff, T.M.A. de Alves, E.M. Souza-Fagundes, F.F. Campos, C.L. Zani, Mem. Inst. Oswaldo Cruz 113, 102 (2018) CrossRef PubMed Google Scholar
  137. 137.
    C.R. Novello, E. Düsman, R.B. Balbinot, J.C. de Paula, C.V. Nakamura, J.C.P. de Mello, M.H. Sarragiotto, Nat. Prod. Res. 0, 1 (2020) PubMed Google Scholar
  138. 138.
    C.B. Naman, A.D. Gromovsky, C.M. Vela, J.N. Fletcher, G. Gupta, S. Varikuti, X. Zhu, E.M. Zywot, H. Chai, K.A. Werbovetz, A.R. Satoskar, A.D. Kinghorn, J. Nat. Prod. 79, 598 (2016) CrossRef PubMed Google Scholar
  139. 139.
    M.G.F. de Medeiros, A.C. da Silva, A.M.G.L. das Citó, A.R. Borges, S.G. de Lima, J.A.D. Lopes, R.C.B.Q. Figueiredo, Parasitol. Int. 60, 237 (2011) CrossRef PubMed Google Scholar
  140. 140.
    V. Smyrniotopoulos, C. Merten, M. Kaiser, D. Tasdemir, Mar. Drugs 15, 1 (2017) PubMed Google Scholar
  141. 141.
    O. Chiboub, I. Sifaoui, J. Lorenzo-Morales, M. Abderrabba, M. Mejri, J.J. Fernández, J.E. Piñero, A.R. Díaz-Marrero, Mar. Drugs 17, 1 (2019) PubMed Google Scholar
  142. 142.
    D.C. Soares, M.M. Szlachta, V.L. Teixeira, A.R. Soares, E.M. Saraiva, Mar. Drugs 14 (2016) PubMed Google Scholar
  143. 143.
    A.R. Díaz-marrero, A. López-arencibia, C.J. Bethencout-estrella, F. Cen-pacheco, I. Sifaoui, A. Hernández, M.C. Duque-ramírez, I. Universitario, D.B.A. González, I. Ag, C. De Investigaciones, B. De Canarias, U. De La, L. Ull, Bioorg. Chem. 92 (2019) PubMed Google Scholar
  144. 144.
    C. Imperatore, R. Gimmelli, M. Persico, M. Casertano, A. Guidi, F. Saccoccia, G. Ruberti, P. Luciano, A. Aiello, S. Parapini, S. Avunduk, N. Basilico, C. Fattorusso, Mar. Drugs 18 (2020) PubMed Google Scholar
  145. 145.
    T. Meza-Menchaca, A. Ramos-Ligonio, A. López-Monteon, A.V. Limón, L.A. Kaluzhskiy, T.V. Shkel, N.V. Strushkevich, L.F. Jiménez-García, L.T.A. Moreno, V. Gallegos-García, J. SuárezMedellín, Trigos, Biomolecule 9 (2019) PubMed Google Scholar
  146. 146.
    S. Mukherjee, W. Xu, F.F. Hsu, J. Patel, J. Huang, K. Zhang, Mol. Microbiol. 111, 65 (2019) CrossRef PubMed Google Scholar
  147. 147.
    L.P. Borba-Santos, G. Visbal, T. Gagini, A.M. Rodrigues, Z.P. De Camargo, L.M. Lopes-Bezerra, K. Ishida, W. De Souza, S. Rozental, Front. Microbiol. 7, 1 (2016) PubMed Google Scholar
  148. 148.
    B. Lomenick, H. Shi, J. Huang, C. Chen, Bioorganic Med. Chem. Lett. 25, 4976 (2015) CrossRef PubMed Google Scholar
  149. 149.
    C. Park, D.O. Moon, C.H. Ryu, B.T. Choi, W.H. Lee, G.Y. Kim, Y.H. Choi, Acta Pharmacol. Sin. 29, 341 (2008) CrossRef PubMed Google Scholar
  150. 150.
    L. Pan, C.M. Lezama-Davila, A.P. Isaac-Marquez, E.P. Calomeni, J.R. Fuchs, A.R. Satoskar, A.D. Kinghorn, Phytochemistry 82, 128 (2012) CrossRef PubMed Google Scholar
  151. 151.
    H.T. Takahashi, E.A. Britta, R. Longhini, T. Ueda-Nakamura, J.C. Palazzo De Mello, C.V. Nakamura, Planta Med. 79, 330 (2013) CrossRef PubMed Google Scholar
  152. 152.
    V. Leliebre-Lara, L.M. Fidalgo, E.M. Pferschy-Wenzig, O. Kunert, C.N. Lima, R. Bauer, Molecules 21, 1045 (2016) CrossRef PubMed Google Scholar
  153. 153.
    E.S. Elkhayat, S.R.M. Ibrahim, G.A. Mohamed, S.A. Ross, Nat. Prod. Res. 30, 814 (2016) CrossRef PubMed Google Scholar
  154. 154.
    G.H. Braun, H.P. Ramos, A.C.B.B. Candido, R.C.N. Pedroso, K.A. Siqueira, M.A. Soares, G.M. Dias, L.G. Magalhães, S.R. Ambrósio, A.H. Januário, R.C.L.R. Pietro, Nat. Prod. Res. 1 (2019) PubMed Google Scholar
  155. 155.
    A.A.S. Silva, S.M. Morais, M.J.C. Falcão, I.G.P. Vieira, L.M. Ribeiro, S.M. Viana, M.J. Teixeira, F.S. Barreto, C.A. Carvalho, R.P.A. Cardoso, H.F. Andrade-Junior, Phytomedicine 21, 1419 (2014) CrossRef PubMed Google Scholar
  156. 156.
    L. Keller, J.L. Siqueira-neto, J.M. Souza, K. Eribez, G.M. Lamonte, J.E. Smith, W.H. Gerwick, Molecules 24, 1604 (2020) PubMed Google Scholar

Copyright information

© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Authors and Affiliations

  1. 1. Department of Chemistry, School of Physical and Mathematical Sciences, College of Basic and Applied Sciences, University of Ghana, P. O. BOX LG 56, Legon, Accra, Ghana
  2. 2. Department of Chemical Sciences, School of Sciences, University of Energy and Natural Resources, Box 214, Sunyani, Ghana
  3. 3. Department of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA
  4. 4. Department of Molecular Pharmacology and Neuroscience, Loyola University Medical Center, Maywood, IL 60153, USA
  5. 5. Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA
  6. 6. Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, PMB LG 77, Legon, Accra, Ghana
  7. 7. Department of Biochemistry, Cell and Molecular Biology, West African Centre for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 54, Accra, Ghana
  • Add: 132# Lanhei Road, Heilongtan, Kunming 650201, Yunnan, China
  • Fax: +86 871 65223223
  • Tel: +86 871 65223223
  • E-mail: npb@mail.kib.ac.cn
  • 0

Copyright © 2017 Natural Products and Bioprospecting, All Rights Reserved.