Natural Products and Bioprospecting (2021) 11:489–544 
https://doi.org/10.1007/s13659-021-00311-2
REVIEW
The Search for Putative Hits in Combating Leishmaniasis: The 
Contributions of Natural Products Over the Last Decade
Patrick O. Sakyi1,2 · Richard K. Amewu1 · Robert N. O. A. Devine2 · Emahi Ismaila2 · Whelton A. Miller3,4,5 · 
Samuel K. Kwofie6,7 
Received: 11 February 2021 / Accepted: 7 May 2021 / Published online: 14 July 2021 
© The Author(s) 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 treat-
ment. 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, I C50/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 avail-
able enriched data pertaining to bioactivity and mechanisms of natural products complement current efforts geared towards 
unraveling potent leishmanicides of therapeutic relevance.
Graphic Abstract
Keywords Chemotherapeutics · Chemoinformatics · Natural products · Cytotoxicity · Leishmaniasis · Phenotypic screening
1 Introduction
The debilitating rate of parasitic infections in the tropical 
and subtropical regions of developing countries has become 
  Samuel K. Kwofie alarming [1]. Vector-borne neglected tropical diseases and *
 skkwofie@ug.edu.gh related synergetic co-infections, particularly leishmaniasis 
Extended author information available on the last page of the article are very challenging and sophisticated to treat [2]. This 
Vol.:(012 3456789)
 490 P. O. Sakyi et al.
is partly due to the existence of diverse parasitic species out parasites came into play. Unfortunately, the presence 
with different bionomics and sophisticated overlap between of persistent lesions and the difficulty in estimating their 
virulent factors. Activated immune response during disease efficacy rendered these approaches less effective [10, 11]. 
exacerbation coupled with emerging resistance by both para- Efforts to alleviate leishmaniasis via chemotherapy include 
sites and vectors against various treatment regimens have the use of pentavalent antimonial, which was essentially a 
also contributed to this challenge [2, 3]. small tartrate complex of antimony first reported in 1925 by 
Leishmania, the etiological agent of leishmaniasis, is Brahmachari [12, 13]. Although, antimoniate  (SbV) is still 
transmitted globally by over 90 different female sand-fly active after reduction by arsenate reductase to  SbIII, Leish-
species of the Phlebotomus family, spread across 98 coun- mania parasites are also susceptible to S bV via oxidative 
tries and four continents, with annual estimates of 1 million stress.
new cases and 30,000 deaths as at 2017 [2, 4]. The exact Gene amplification studies involving the Adenosine 
disease burden is unknown, but statistics indicate that over Triphosphate (ATP) binding cassette transporters including 
350 million people are at risk, signifying a prominent public the multi-resistance proteins that act as efflux pumps have 
health risk [2, 5, 6]. been shown to contribute to antimony resistance in clinical 
Leishmaniasis is curable if the disease is diagnosed early isolates [14, 15]. Likewise, deletions of aquaporin mem-
and the appropriate medication is administered. Typically, brane carrier genes and phenotypic changes of the parasite 
leishmaniasis is initially marked by dermotropic ulcers, with subsequent induced effects on the microbicide activity 
which then progress into the visceral tissues, resulting in and the efflux rate of antimony reaching the macrophages 
a late and more debilitating condition that can often lead also contribute to the resistance [16].
to death if left untreated. In some cases, the destruction of In the mid-1960’s pentamidine became the second choice 
the mucocutaneous membrane especially the nose, throat, to antimony resistant strains [17]. However, its utility like 
and mouth have also been very common [2]. The degree of the antimonial was hampered due to severe vasomotor side 
clinical outcome and its corresponding immunopathology effects and complex interactions with the pancreas which 
depends primarily on the type of causative species, age of leads to the destruction of β-cells causing diabetes mellitus 
host, and the balance between the host immune response [17].
and how the parasites subvert these defense mechanisms. In In the quest to expedite the time it takes for drugs to reach 
cases where the victim’s immune system is strong, Leishma- the market, strategies such as deciphering the cellular simi-
nia pathogens behave as opportunists by remaining dormant larities between disease causing pathogens from phenotypic 
until the host’s immunity is compromised. Additionally, screening were developed. In the early 1960s, the anti-fun-
when the host is immunosuppressed, relapses are usually gal amphotericin B from Streptomyces nodosus was used 
prevalent resulting in treatment failures. for treating leishmaniasis [18, 19]. This choice was widely 
Some challenges associated with the management of accepted in most endemic areas due to its efficacy but not so 
leishmaniasis include systemic toxicity of administrated in other areas especially East Africa (L. donovani) and South 
drugs, high cost of existing therapeutic options, lengthy America (L. infantum) [20].
treatment periods and drug resistance. Furthermore, con- The anticancer agent alkyl phosphocholine (miltefosine) 
founding factors such as parasite diversity has hampered was the first oral formulation with strong protection against 
various intervention strategies and halted global efforts, visceral leishmaniasis. Miltefosine works by modulating an 
necessitating an immediate search for new drug leads for apoptosis process induced by mitochondria membrane depo-
development as the next generation of antileishmanial agents larization and phospholipid biosynthesis inhibition [21]. The 
[7–9]. In lieu of this, the review seeks to bring to the fore the main drawback in administering miltefosine for leishmania-
various classes of natural products recently discovered with sis treatment includes longer elimination time, lengthy treat-
antileishmanial potentials over the last decade. Even though, ment course, and miscarriage in pregnant patients after use 
the review primarily reported compounds with potent bioac- [22].
tivity, few with low potency were reported since these could A new and simple formulation of an old antibiotic paro-
be optimized or their scaffolds may serve as skeletons for the momycin which inhibited translation with different modes 
development of future leishmanicides. of application (enteral, parenteral and topical) was also 
repurposed for leishmaniasis in 1967 [23, 24]. Unlike the 
1.1 T rends in leishmanial chemotherapy other treatment options, paromomycin’s toxic effects are 
and current panorama very minimal, but its efficacy is quite poor. New optimum 
carriers targeting pathogen macrophage using albumin has 
Protection against leishmaniasis started with mimicking nat- recently been reported to increase efficiency [25].
ural immunity through live inoculations [10] until modern- Following the failure of miltefosine, a collaboration 
ized techniques including killed promastigotes and knocked between the Walter Reed Army Institute of Research 
1 3
The search for putative hits in combating leishmaniasis 491
(WRAIR, USA) and GlaxoSmithKline (UK) identified sita- 1.3 C lassification of natural products 
maquine as a promising alternative, but its apparent loss of with anti‑leishmania properties
efficacy in tegumentary leishmaniasis limited its use [26]. 
Subsequently, findings from amphotericin B use and its high 1.3.1  Alkaloids
curative rate in patients influenced another repurposing strat-
egy using the oral anti-fungal azoles (fluconazole, itracona- Among the characterized bioactive constituents from nature, 
zole, and ketoconazole) as suitable control and cost-effective alkaloids have provided a broad-spectrum activity against 
therapy [27, 28]. different ailments and demonstrated their suitability as 
Due to the therapeutic challenges, new chemotypes with potential drug leads. Phenotypic alterations in ultrastructure 
high potency in tandem with immunostimulatory activity form of the infective cells and immunomodulatory investi-
targeting new proteins applicable to both visceral and cuta- gation studies of isolated alkaloids within the last decade 
neous leishmaniasis cases are desperately needed. reveal 27 alkaloids (Table 1) with varying efficacies from 
strong to weak activity. The natural product 3 isolated from 
1.2  Natural products as possible sources of new Cissampelos sympodialis acts as a calcium channel inhibitor 
drugs against leishmaniasis with immunomodulatory effects through the enhancement of 
nitric oxide (NO) production in macrophages [52]. Studies 
The lack of effective vaccines for control and concerted of 4 from Croton pullei reported significant alterations in 
elimination campaign [2], and recent snail paced progress organelle membranes of the endoplasmic reticulum, kino-
on leishmanial vaccine development does not guarantee plast and golgi body, depicting an apoptosis-like process 
any optimism. With the advancements in synthetic organic [53]. Treatment with spectaline alkaloids, 16 and 17 from 
chemistry, combinatorial chemistry, and computational de dichloromethane fractions of the flower Senna spectabilis of 
novo drug discovery strategies, as well as high throughput Leishmania promastigotes also portray a similar molecular 
screening techniques, only a few synthetically constructed mechanism like its structurally related piperine amide alka-
drugs have been useful in combating leishmaniasis. Even loid, which either modulates the sterol biosynthetic pathway 
with this, few natural product scaffolds represent major phar- or acts as an inhibitor of cell proliferation by mitochondrion 
macophores responsible for their curative effects. Between organelle destruction [54]. Although, the exact mode of 
2005 and 2010, about 19 natural products were registered action has not been fully elucidated, 21 from Berberine vul-
for treatment of infectious diseases [29]. Similarly, over 69% garis like the active alkaloid in Berberine aristate perpetu-
of new small molecules used for the treatment of infectious ates a similar activity through respiration incapacitation and 
diseases originated from natural products [30, 31]. apoptosis [55]. However, 21 was identified as a potential cell 
Despite the large molecular weights of natural products membrane disruptor via sterol biosynthesis inhibition [56], 
which renders some of them less druglike, structural diver- while 22 induces reactive oxygen species (ROS) generation. 
sity, large chemical space and safety are characteristics that Structural activity relation (SAR) studies of high affinity 
overrides synthetic alternatives. Treatments using extracts protein kinase inhibitors, staurosporine-based compounds 
from plant families from endemic regions include Fabaceae (24-27) revealed the 4th C methyl amine and 7th C hydrogen 
[32], Annonaceae, Euphorbiaceae [31, 33, 34], Rutaceae acceptor as the cause for the reinforced activity observed 
[35–37], Myrsinaceae [31, 38], Liliaceae [39], Araliaceae in L. donovani, which had major morphological changes in 
[38], Simaroubaceae [40], as well as endophytes gen- the flagella pocket and plasma membrane because of signal 
era Alternaria [41], Arthrinium, Penicillium, Cochloibus, blockage via phosphokinase (PK) inhibition.
Fusarium, Colletotrichum, and Gibberella [42]. Addition-
ally, the exploration of marine natural products has led to 1.3.2 P henolics
the identification of interesting natural products with diverse 
biomolecular functions [43, 44]. As characterized by hydroxy-phenyl groups, polypheno-
Since the mid-eighties when the search for anti-leishma- lics are widely distributed in nature and have been isolated 
nial natural products became prominent, numerous metabo- from different plants. In traditional medicine phenolics have 
lites originating from plants to current antileishmanial thera- received much interest in phyto-therapeutics for the treat-
pies have been reported. Lately, credible chemical entities ment of ailments ranging from non-infectious to infectious 
from marine sources and endophytic species have also been diseases. These chemotypes include compounds like cou-
reviewed [45–51]. This review presents the various classes marins, flavonoids, quinones, lignans, flavone glycosides 
of natural products from both flora and fauna that have been amongst others (Table  2). Flavonoids from Selaginella 
isolated over the last decade with anti-leishmanial proper- sellowi when tested against different forms of Leishmania 
ties. Also, the  IC50/EC50 values and suggested mechanisms revealed a pro-drug mechanism for 28 but an activated NO 
of action of these natural products are discussed. generation for 29 [70]. The difference in the mode of action 
1 3
4 92 P. O. Sakyi et al.
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 IC50/μg/mL Organism tested Toxicology References
natural 
product
Paenibaccillus sp. Imidazole 28.1 L. donovani Low toxicity profiles to [57]
(Marine)
+ N (Promastigote) mouse macrophages N O RAW 264.7 cell 
lines. > 250 µM
Paenidigyamycin G, 1
  
Paenibaccillus sp.   0.203 L. major MIC = 25 μM [58]
(Marine) (Promastigote)
Imidazole
1.90 L. donovani
N (Promastigote)N+
N+N
Paenidigyamycin A, 2
Cissampelos sympo-   Isoquino- 80.0 L. chasi IC50 = 0.056 μM against [52]
dialis OCH3 line (Promastigote) human laryngeal can-
N OH cer cells (HEP-2cells) 
and 0.067 μM against 
O human mucoepide 
CH cells (NCIH-292)2
O
HO CHN 3
H3CO
Warif teine, 3
Croton pullei var.   Piperidine 6.27 L. amazonensis Nontoxic as against [53]
glabrior O (Amastigote) murine macrophages 
NH after treatment with 
N
O 79 µM of julocrotine
O
Julocrotine, 4
1 3
The search for putative hits in combating leishmaniasis 493
Table 1  (continued)
Natural product source Chemical structure Class of IC50/μg/mL Organism tested Toxicology References
natural 
product
Aconitum spicatum   Pyrrolidine L. major No toxicity against MCF7, [59]
HO HeLa, PC3 cancer cell O lines and 3T3 normal 
O O fibroblast cell line at 
30 µM
O
N R2 56.0
R1
36.1
O
O
Chasmacotine, R1= R2=OAc, 5
Ludaconitine, R1=OH, R2= OH, 6
Helietta apiculata Quinoline 17.3 L. donovani [60]
Quinoline 25.5
Thalictrum alpinum R1 [61] O N  
MeO
MeO OMe
Me
N O
OMe 0.175
OR2 Isoquinoline 0.639 L. donovani
6.60
Northalrugosidine, R1= R2= H, 9
Thalrugosidine, R1= Me, R2= H, 10
Thalidasine, R1= R2= Me, 11
1 3
 494 P. O. Sakyi et al.
Table 1  (continued)
Natural product source Chemical structure Class of IC50/μg/mL Organism tested Toxicology References
natural 
product
Trichosprum sp. Piperazine 96.3 L. donovani [62]
Piperazine 82.5 L. donovani
Piper choba Amide 16.0 L. donovani CC50 = 0.76 μM and [63]
(Promastigotes) 0.83 μM against brine 
shrimp cells
Amide 30.0
Senna spectabilis HO Piperidine 24.9 L. major No observed lethality [54]
CH (Promastigotes) against J774 murine H3C N 3
H macrophageO
Cassine, 16
HO +
CH
H3C N
3
H
Spectaline, 17 O
Aspidosperma rami-   Indole 18.5 L. amazonensis [64]
florum NH (Promastigotes)
H
NH
H
N
H3C
H3CO
H-17α- ramif lorine A, 18
H-17β- ramif lorine B, 19
12.6
1 3
The search for putative hits in combating leishmaniasis 495
Table 1  (continued)
Natural product source Chemical structure Class of IC50/μg/mL Organism tested Toxicology References
natural 
product
Beilschmiedia alloio-   quinoline 2.95 [65]
phylla OH
H3CO N
CH3
2-hydroxy-9-methoxyaporphine, 20
Berberis vulgaris   Isoquinoline 2.10 L. major Observed toxicity against [66]
O 2.90 L. tropica murine macrophage was 
O (Promastigotes) at 9.18 μM
N+
O
O
Berberine, 21
Piper longum   Amide 9.12 L. donovani Test against J774A.1 [67]
(promastigotes) cell line indicated a 
high cytotoxicity at 
HN 5.05 ± 0.64 μg/mL.393
O
2.81 L. donovani
(amastigotes)
O
O
Piperlongumide, 22
Spongia sp. and Ircinia OH Indole 9.6 Toxicity profile against [68]sp. mammalian L6 cells was
(Marine)
N
H
Tryptophol, 23
  
1 3
4 96 P. O. Sakyi et al.
Table 1  (continued)
Natural product source Chemical structure Class of IC50/μg/mL Organism tested Toxicology References
natural 
product
Streptomyces sanyensis O 0.0075 L. amanzon- The series showed low [69](Marine) HN ensis selectivity against 
  O (promastigotes) murine macrophage 
Indolocar- J774A.1 with  CC50 
bazole of 5.20
N
H 0.0012 L. donovaniN (promastigotes)
O
O HN 0.0002 L. amanzon-
ensis
7-oxostaurosporine, 24 (amastigotes)
HN
O 0.00017 L. amanzon- 8.74
ensis
Indolocar-
N (promastigotes)bazole
N 0.0045 L. donovani
O
H O (promastigotes)
HN 0.0224 L. amanzon-
ensis
Staurosporine, 25 (amastigotes)
HN
O 0.037 L. amanzon- > 40
ensis
N Indolocar-
(promastigotes)
N bazole > 0.089 L. donovani
O O (promastigotes)H
O 0.005 L. amanzon-
ensis
40-demethyl-40- (amastigotes)
oxostaurosporine, 26
HN
O Indolocar- 0.0224 L. amanzon- > 40
bazole ensis
(promastigotes)
N
N O
H O > 0.089 L. donovaniO (promastigotes)
Streptocarbazole B, 27
1 3
The search for putative hits in combating leishmaniasis 497
of these two flavonoids may be due to their conformational amazonensis and L. infantum [107]. Effects of clerodone 
orientations. Similar investigations to understand the pos- terpenes, 88, 89 and 90 from the stem bark of Croton caju-
sible cause of apoptosis induced by 30 and 31 suggested a cara have been shown to obstruct ROS protection via tryp-
mitochondrial dysfunction with no influence on ROS [71]. anothione reductase inhibition [108].
However, evidence from suicidal action of some querce- Interest in marine natural products which led to the eval-
tin analogues have also indicated iron chelation, arginase uation of marine terpenes like pentacyclic triterpene 92, 
inhibition, and topoisomerase II intercalation as possible which exhibited an anti-inflammatory action with enhanced 
mechanisms [72]. From the same Nectandra genus, inhibi- levels of T cells and Th1 cytokines when compared to its 
tory activity of 34 and 43 have been fully elucidated. Results control [109].
indicated an inactivation of exacerbatory immunogens with Elucidation of the exact mechanism of action of four trit-
reduced calcium levels and depolarized mitochondria poten- erpenes from the roots of Salvia deserta showed that despite 
tial [73]. Studies with similar compounds against mela- the strong antioxidant capacity of 93, it also kill parasites 
noma cells indicated an apoptosis process confirming the by inhibiting isopentenyl diphosphate condensation with 
depolarization activity [74]. Deciphering the exact mech- the major target being farnesyl diphosphate synthase [110]. 
anism underpinning the leishmanicidal action of isolated Studies to also understand the molecular basics of 94 shows 
compounds from Connarus seberosus, it was revealed that a similar action like 80, but fragmentation of DNA strands 
defects in the mitochondria and plasma membrane structure has been described for diterpene 95 and 96 [111, 112]. Inhi-
with the evidence of lipid accumulation were caused by 55 bition of oxidative pathways particularly IFN-γ-related sign-
and 56 [75]. Comparing 58 and its 3-O-methyl analog, 59, aling by similar diterpenoid quinones isolated from the roots 
to rosmarinic acid (based on the shared catechol nucleus), of Salvia officinalis has also been shown to prevent disease 
their potential mode of action is suggested as inhibition of proliferation and further protecting the host specie [113]. 
reactive oxygen species [76, 77]. 75 as a chemo-preventive Recent studies in estimating the role of the energy produc-
agent acts by reducing inflammatory symptoms by suppress- tion in the form of ATP in Leishmania with acyl phloroglu-
ing NF-κB expression and other pro-inflammatory factors cinol derivatives has revealed 97 as a mitochondria complex 
including iNOS, COX-2, TNF-α, IL-1β, and IL-6 [78]. Com- II/III inhibitor [114].
pound 74 emulates an apoptosis induced suicidal mecha- Like terpenes which are formed by the head to tail con-
nism which involves DNA fragmentation, inhibition of densation of isoprene units, terpenoids (terpenes with oxy-
inflammation cytokines and the activation of caspases with gen-containing functional group) also represent a unique 
downstream effects on gene transcriptional process [79]. group of natural products with high functionalization and 
Structural similarities of anti-inflammatory coumarins with promising pharmacological activity. Isolation of six ger-
74 precludes a similar mechanism of action [80]. From the macranolides from the leaves and stems of the Calea spe-
isolates of Arrabidaea brachypoda only 67 altered organelle cies have shown promising activities against L. donovani 
structure and function by attenuating cytoplasm puncturing and L. amazonensis [115, 116]. Among them morphologi-
and golgi apparatus swellings [81]. cal assessment studies with 100 and 111 indicated altera-
tions in the nucleus and mitochondria describing an apop-
1.3.3  Terpenes and terpenoids tosis like process through the mitosis motor downregulation 
pathway [115]. Due to the similar core structure shared with 
Another group of secondary metabolites with interesting germacra-1(10),11(13)-dien-12,6-olide a similar mechanism 
anti-parasitic activities are terpenes. Ultrastructural changes is envisaged for its counterpart 104 by aiding in generating 
of 79 in phenotypic screenings indicated mitochondrial blebs ROS complementing the elucidated apoptosis process. The 
and lipid deformities [100, 101]. 80 isolated from essential natural product 106 shares same structural core therefore may 
oils of Tetradenia riparia were found to distort promastigote possess similar mode of action in addition to the inhibition 
structure especially the fate of its chromatin followed by an of thiol-antioxidant enzymes [117]. Interestingly, 106 and 
apoptosis process which is suspected to be caused by cas- its iso-conformer have also been disclosed to induce a pro-
pase activation [102, 103] (Tables 3 and 4). inflammatory inhibition via the NF-KB pathway [118]. On 
Halogenated terpenes 72 and 83 from Laurencia den- the other hand, 110 and 125 have also exerted multi-spectral 
droidea which only differ primarily in a double bond char- activities including suppression of cell proliferation modula-
acter also targets the same organelle via redox perturbation tors and upregulation of microbicidal NO species [119].
[104, 105]. The natural product 87 from Vanillosmopsis 
arborea show promising activity through apoptosis induc- 1.3.4 S teroids
tion characterized by mitochondrial dysfunction and oxida-
tive stress [106]. Similar mode of action was reported for Steroids are a class of natural or synthetic organic com-
87 isolated from Tunisia chamomile essential oil against L. pounds with three six membered rings fused with a five 
1 3
4 98 P. O. Sakyi et al.
1 3
Table 2  Various classes of phenolic compounds with their I C50 exhibiting antileishmanial properties
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Selaginella sellowi OH O Flavonoid 0.10 L. amazonensis IC50 = 5.57 and 4.09 µM [70]against Murine 
macrophages (J774.
A1) and fibroblast cells 
HO O (NIH/3T3)
OH
OH
HO O
OH O
Amentoflavone, 28
 
OH Flavonoid 2.80 CC50 = 5.75 and 47.4 µM 
O
HO against murine macrophage (J774.
O HO A1) and fibroblast cells 
(NIH/3T3).
O
OH
OHHO
O
Robustaf lavone, 29
The search for putative hits in combating leishmaniasis 499
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Strychnos pseudoquina OH Flavonoid 11.9 L. infantum Low-toxicity to infected [71]
O 2.02 L. amazonensis murine macrophage 
O up to 125 μM and low 
OH OH hemolytic activity in red blood cells
HO O
HO O
OH
OH O
OH O
Strychnobif lavone, 30
 
OH
HO O
OH Flavonoid 2.56 L. amazonensis No significant toxic-ity > 199 μM
O
OH O
Quercetin 3-metyl ether, 31
 500 P. O. Sakyi et al.
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Lendenfeldia. dendyi and 
Sinularia dura OH OCH
Phenyl ether 18.0 L. donovani Low toxicity profile to [82]
3 (Promastigotes)t VERO cells, pig kidney 
(Marine) Br O Br epithelia, human dermal 
carcinoma oral
Br Br
Br
2,3,5-tribromo-6-(3,5-dibromo-2-
methoxyphenoxy)phenol, 32
 
OCOCH3 OCOCH3 Phenyl ether 13.6 L. donovani Ductile carcinoma breast, 
Br O Br human malignant mela-
noma up to 13 µM
Br Br Br
Br
2-(2-acetoxy-3,4,5-tribromophenoxy)-
3,5,6-tribromophenyl acetate, 33
Nectandra leucantha Phenyl ether 8.70 L. donovani Nontoxic to mammalian [83]
O 6.00 (Intra Amastigotes) peritoneal macrophages 
R1 34.9 up to
>293.8 μM
112.1 μM
O >292.1 μM
R2 O
Dehydroeugenol B, R1= OH, R2 = H, 34
1-(8-propenyl)-3-[31-methoxy-11-(8-propenyl)phenoxy] -4,5-dimethoxybenzene, R1 = OMe, R2 = H,
35
1-(7R-hydroxy-8-propenyl)-3- [31-methoxy-1-(81-propenyl)- phenoxy]-4-hydroxy-5-
methoxybenzene, R1 = OH, R2 = OH, 36  
The search for putative hits in combating leishmaniasis 501
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Alpinia galanga R O Monolignols 10.5 L. donovani [84]1 16.6 (Promastigotes)
CH2OR2
p-coumaryl diacetate R1 = R2 = OAc, 37
trans-p-acetoxy cinnamyl alcohol R1 = OAc = R2 = H, 38
 
AcO
Phenol ester 8.80
R 5.60
OAc
1'-acetoxychavicol acetate R = H, 39
1'-acetoxyeugenol acetate R = OMe, 40
Hellieta apiculata Coumarin 35.8 L. amazonensis [60]
HO 27.5 L. infantum
H 32.1 L. brazilensis
O O O
3-(1'-dimethylallyl)-decursinol, 41
Coumarin 18.5 L. amazonensis
27.4 L. infantum
 21.5 L. brazilensis
HO O O O
Heliettin, 42
 502 P. O. Sakyi et al.
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Nectandra oppositifolia O Butanolide 3.58 Nontoxic against NCTC [85]
HO cell up to 42.3 µM
O
O
Secosubamolide-A, 43  
Piper regnellii var. pallescens O Lignan 5.00 L. amazonensis [86]
OH
O
Eupomatenoid-5, 44
 
The search for putative hits in combating leishmaniasis 503
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Nectandra cuspidata OH Flavonoid 38.5 L. amazonensis Low cytotoxicity in J774. [87](Amastigotes) A1 macrophages
HO O
OH
OH
OH
Flavan-3-epicatechin, 45
 
OH
HO
OH
O OH
HO Flavanoid 71.3
HO O
OH O
Vitexin, 46
Flavanoid 34.0
OH
HO O
O
HO
OH O
HO OH
OH
Isovitexin, 47
5 04 P. O. Sakyi et al.
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Plumbago zeylanica O Quinone 1.05 L. donovani Very toxic to on RAW [88]
(EC50) (Amastigotes) 264.7 macrophage cell 
lines
O O
2-methyl-5 -(3-methyl-but-2-enyloxy)-
[1,4]naphthoquinone, 48  
Ocimum gratissimum Monolignol 0.81 L. infantum Nontoxic in murine mac- [89–91]
HO rophages RAW 264.7 
cells lines 29.0 µM
O
Eugenol, 49
 O
O
OH Monolignol 18.5 >100 µM
Acetyl-Eugenol, 50
O
O
Monolignol 14.9 97.7 µM
OH
Benzoyl-Eugenol, 51
The search for putative hits in combating leishmaniasis 505
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Vernonia polyanthes Quinone 50.5 L. amazonensis At conc. > 52.4 µM in [92]
OH (Promastigotes) infected murine mac-
O rophages
O
H
O O
O
O
 
Anhydrocochlioquinone A, 52
OH
O OH
H O Quinone 10.2 At conc. > 37.23 µM in 
H infected murine mac-
O O rophages
O
O
Cochlioquinone A, 53
+
OH
OH O
H
O
H
O O
OH
O
Isocochlioquinone, 54
5 06 P. O. Sakyi et al.
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Connarus Suberosus Chromanone 1.13 L.amazonensis Toxic at 18.3 µM against [75]
(amastigotes) murine macrophages.
 
4.5 L. amazonensis
OH (promastigotes)
5.2 L.infantum (promastig-
HO O otes)
Connarin, 55
O Lignan 11.4 L. amazonensis Reduction cell viability 
(promastigotes) was at 116 µM.
O
O 15.5 L.infantum (promastig-
otes)
O 7.1 L. amazonensis
(promastigotes
O
Leiocarpin, 56
The search for putative hits in combating leishmaniasis 507
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Piper aduncum O Lignan 0.31 L. amazonensis Critical changes in the [93](promastigote morphology of 3T3 
fibroblast cell lines 
O O and its viability was observed at 25 µM and 
O above.
Dillapiole,57 )
 0.28 L. braziliensis
(promastigotes)
Hyptis pectinata OH Flavonoid 2.5 L. braziliensis N.T [76]
O (promastigotes)
HO COOH
O
OH
HO
Sambacaitaric acid, 58
O
O
O
O O COOH
O
O O
 O Flavonoid >36.0
O
3-O-methyl-sambacaitaric acid, 59
Geosmithia langdonii OH Phenyl propene 0.05 L. donovani N.T [94]
OH (promastigotes)
HO OH
OH
4-(2,4-dihydroxy- 6(hydroxymethyl)benzyl)
benzene-1,2-diol,60  
 508 P. O. Sakyi et al.
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Geosmithia langdonii OH Carbasugar 0.34 L. donovani N.T [95]
HO OH Carbasugar 0.20 (promastigotes)
O
HO
O
OH
(1S,2R,3R,4R,5R)-2,3,4-trihydroxy-5-
methylcyclohexyl-2,5-dihydroxybenzoate, 61  
The search for putative hits in combating leishmaniasis 509
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Ferula narthex HO Coumarin 43.77 L. amanzonensis N.T [96]
OH (promastigotes)
HO O
OH
HO
(1S,2S,3S,4R,5R)-4-[(2,5-dihydroxybenzyl)
oxy]-5-methylcyclohexane-1,2,3-triol, 62
 
H
O O O
O
Fnarthexone, 63
Coumarin 46.81
H
O O O
HO
Fnarthexol,64
H
O O O
Coumarin 11.51
HO
Conferol, 65
O O O
O
Conferone, 66
Coumarin 46.77
5 10 P. O. Sakyi et al.
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Arrabidaea brachypoda O OH Flavonoid 0.004 L. amanzonensis High lethality against [81]
(amastigotes) macrophages at concen-
tration above 20 μM
HO O 0.017 L. amanzonensis
(promastigotes)
O
0.013 L. brazilensis
O (promastigotes)
0.024 L. infantum
(promastigotes)
O
Brachydin B, 67
O OH
Flavonoid 0.02 L. amanzonensis
HO O (amastigotes)
O 0.017 L. amanzonensis(promastigotes)
O 0.037 L. brazilensis
(promastigotes)
0.012 L. infantum
(promastigotes)
Brachydin C, 68
 
The search for putative hits in combating leishmaniasis 511
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Trixis antimenorrhoea O Flavonoid 78 L. amazonensis N. T [97]
O (promastigote)
HO O
96 L. brazilensis
O (promastigote)
OH O
Nevadesin, 69
O
O O 19
O
O O Flavonoid 5.8
OH O O
5-hydroxy-3,3,4,6,7,8-
hexamethoxyflavone, 70
 
Anogeissus leiocarpus OH Flavonoid 0.003 L. donovani CC50 > 100 µg/ml [98](promastigotes)
HO O
OH
O
OH O OH
O
O O
OH
OH
HO OH
OH
Rutin, 71
 
 512 P. O. Sakyi et al.
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Sassafras albidum O Lignan 15.8 L. amazonensis Nontoxic against BALB/c [36]
O H (Promastigote) mouse macrophages up to
O O 282
H O
O
Sesamin, 72
O
O Lignan 45.4 190
O O
O
O
Spinescin, 73
 
The search for putative hits in combating leishmaniasis 513
1 3
Table 2  (continued)
Natural product source Chemical structure Class of phenolic IC50/μg/mL Organism tested Toxicology References
Zanthoxylum tingoassuiba Coumarin 57.7 L. amazonensis N. T [99]
O (Promastigote)
O O O
O
 5,7,8-trimethoxycoumarin, 74
O
O Coumarin 70.0
O
O
Braylin, 75
O OH Lignan 12.0
O
O O
O
HO O
Syringaresinol, 76
5 14 P. O. Sakyi et al.
Table 3  Various classes of terpenes and terpenoids with their I C50 exhibiting antileishmanial properties
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Parinari excelsa Triterpenoid 0.05 L. donovani Cell viability assay [120]
(amastigotes) with L6 cell lines 
revealed the lethal 
H concentration at 73.5 μg/mL
H
OH
H
O
H
16-hydroxylupane-1,20(29)-
dien-3-one, 77
 
Morinda lucida H3CO2C Monoterpenoid 1.17 L. donovani [121](promastig-
otes)
O
O O OCH3
O OH
Molucidin, 78
 
Canistrocarpus AcO OH Diterpene 4.00 L. amazon- Non-toxic up to [100]cervicornis ensis 515 µM in human 
(Marine) (Intra Amas- macrophage strains 
tigotes) J774G8
OH
(4R,9S,14S)-4a-acetoxy-9b,14a-dihydroxydolast-
1(15),7-diene, 79  
Tetradenia riparia Sesquiterpene 2.45 L. amazon- high toxicity [122]
ensis against mouse 
(Promastig- peritoneal mac-
otes) rophages = 1.69 µM
HO
O
O
6,7-Dehydroroyleanone, 80
 
1 3
The search for putative hits in combating leishmaniasis 515
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Laurencia den- Sesquiterpene 10.8 L. amazon- CC50 in macrophages [123]
droidea ensis and lymph nodes in 
(Marine) (Intra Amas- amastigotes cervical 
HO tigotes) BALB/c mice
160.2 and 172.8 µM
H
Triquinane, 81
 
Br
Sesquiterpene 1.50 112.9 and 120.2 µM
Cl
HO
Elatol, 82
Sesquiterpen 1.62 133.5 and 139.3 µM
Br Br
Cl
HO
Obtusol, 83
1 3
5 16 P. O. Sakyi et al.
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Combretum Triterpene 3.30 L. amazon- Non-toxic against [124]t
leprotum ensis mouse peritoneal 
(Promastig- macrophages
otes)
HH
H
OH
HO
H
OH
3, 6, 16-trihydroxylup-20(29)-ene, 84
 
Triterpene 3.48
HH
H
O
O
H
O
3, 6, 16 -trioxolup-20(29)-ene, 85
Triterpene 5.80
HH
H
OH
HO
H
O
3,16-dihydroxy-6oxolup-20(29)-ene, 86
Vanillosmopsis HO Sesquiterpene 10.7 L. amazon- Low cytotoxicity [106]arborea ensis to macrophage 
(Amastigotes) J774.G8 cell lines 
451 µM
α–Bisabolol, 87  
1 3
The search for putative hits in combating leishmaniasis 517
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Croton cajucara O Diterpene 20.0 L. amazon- [108]ensis
(Axenic Amas-
tigotes)
O
O
O H
H
 trans-dehydrocrotonin, 88
O
Diterpene 41.4
O
O H
O
H
trans-crotonin, 89
H Triterpene 58.3
H OH
O O
O
H
Acetyl aleuritolic acid, 90
Croton sylvaticus HO O Diterpenoid 10.0 L. major Observed toxicity was [125](Promastig- low at 247.83 µM
otes)
H
O
Harwickic acid, 91
 10.0 L. donovani(Promastig-
otes)
1 3
 518 P. O. Sakyi et al.
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Sterculia villosa Triterpenoid 15.0 L. donovani N.T [126]
(Intracellular 
Amastig-
H otes)H
H
HO
H
Lupeol, 92
 
Salvia deserta Diterpenoid 0.46 L. donovani N. T [35]
OH
 
H
Taxodione, 93
O
HO
Diterpenoid 3.30
H
O
Ferruginol, 94
OH
O
7.40
O Diterpenoid 29.4
R
7-O-Acetyl Horminone, R= OAc, 95
Horminone, R= H, 96
1 3
The search for putative hits in combating leishmaniasis 519
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Garcinia acha- Monoterpenoid 10.4 L. amazon- N. T [127]
chairu ensis
O OH
OH
18.4 L. brazilensis
O O OH
Guttiferone A, 97
 
Rapanea fer- 24.1 L. amazon- N. T [127]
ruginea ensis
OH
6.10 L. brazilensis
O
O
OH
Myrsinoic acid B, 98
 
1 3
5 20 P. O. Sakyi et al.
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Calea zacatechichi O Sesquiterpene 1.89 L. donovani [116]
Lactone
O O
O
HO O
O
 O
Calealactone D, 99
O
O O
O
HO O Sesquiterpene 0.771
O Lactone
O
Calealactone C, 100
HO O O
O
O OO Sesquiterpene 0.898Lactone
O
O
Calein D, 101
O O O
O Sesquiterpene 1.74
HO O Lactone
O
O
O
Calein A, 102
O O
HO O Sesquiterpene 3.09
O Lactone
O O
Calealactone E, 103
O O
O
Sesquiterpene 1.60
O O Lactone
OO
O
O
8β-angeloxy-9α-acetyloxy-
calyculatolide, 104
1 3
The search for putative hits in combating leishmaniasis 521
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Tanacetum parthe- Sesquiterpene 2.60 L. amazon- Low toxicity towards [128]
nium Lactone ensis J774G8 cells
O (promastig-HHO O otes)
H
Parthenolide, 105
 
Plumeria bicolor O Monoterpene 0.409 L. donovani CC50 = 20.6 µM [129]
H lactone (Amastigotes)O O
O
 H
O O H
H
Plumericin, 106
O O
O
H Monoterpene 1.19 CC50 = 24 μM
O LactoneH
O H
O H
Isoplumericin, 107
1 3
 522 P. O. Sakyi et al.
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Pseudelephanto- Sesquiterpene 0.0794 L. amazon- High selectivity [130]
pus spicatus lactone ensis towards parasites as 
compared to mam-
HO O O malian cells with
O >100, > 100 µM HO and > 100 µM µM 
 O against Hela, L929 O O and B16F10 cell 
lines
O
8,13-diacetyl-piptocarphol, 108 58.5 µM, > 100 µM and > 100 µM 
against Hela, L929 
and B16F10 cell 
lines
Toxic towards 
RAW264.7, 
HONE-1, KB and 
O HT 29 cell lines O
HO O with 15.6 µM, 8.8 µM,8.2 µM and 
4.7 µM respectively
HO O O Sesquiterpene 0.142
O lactone
8-acetyl-13-O-ethyl-piptocarphol, 109
H
Triterpenoid 0.451
H OH
O
HO
H
Ursolic acid, 110
1 3
The search for putative hits in combating leishmaniasis 523
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Calea pinnatifida Sesquiterpene 1.73 L. amazon- At 4.11 µM, toxic to [115]
 Lactone ensis J774 macrophages
O (Promastig-HO O otes)
O
L. amazon- 75.5 µM
ensis
O OO (Amastigotes)
O
O
Calein C, 111
O
Sesquiterpene
O O lactone 4.24
O
HO O
O
O
Calealactone C, 112
1 3
5 24 P. O. Sakyi et al.
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Spongia sp. and Diterpene 0.75 L. donovani Toxicity profile [68]
Ircinia sp. O against mammalian 
(Marine) Ac L6 cells was
 O
11β-acetoxyspongi-12-en-16-one,113 9.64
HO
OH
O
Sesterterpene 5.60 127
4-hydroxy-3-octaprenylbenzoic acid, 114
OH O
O Sesterterpene 4.80 83.1
Furospongin-1, 115
O Sesterterpene 10.2 > 217
OH
O COOH
Demethylfurospongin-4, 116
O
COOH Triterpene 15.9 >146
HO
2-(hexaprenylmethyl)-2-methylchromenol, 117
O
Sesterterpene 14.2 >254
Furospinulosin-1, 118
OH
Tetraterpene 18.9 4.36
OH Heptaprenyl-p-quinol, 119
1 3
The search for putative hits in combating leishmaniasis 525
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Baccharis tola Diterpenoid 4.60 L. brazilensis All compounds [131]
OH showed high cyto-toxicity in human 
U937 macro phages 
 with values lower 
than 347 μM
Ent-beyer-15-en-18-ol, 120
OH
Diterpenoids 5.30
Ent-beyer-15-en-19-ol, 121
Jatropha muitifida Diterpenoid 11.9 L. donovani Low toxicity profile [132]
HO H against VERO cells
H
 O OH
14-deoxy-1β-hydroxy-4(4E)-
jatrogrossidentadione, 122
HO H
Diterpenoid 4.69
H
HO H OH
15-deoxy-1β-hydroxy-4(4E)-
jatrogrossidentadione, 123
O
HO H
H Diterpenoid 4.56
HO H OH
Unsaturated ring A of 15-deoxy-1β-hydroxy-
4(4E)-jatrogrossidentadione, 124
1 3
5 26 P. O. Sakyi et al.
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Psidium Guajava Triterpene 1.01 L. infantum At conc. = 12.2 µM in [133]
(Axenic Amas- mouse macrophage 
tigotes) cell lines J774A.1
 
H
OH At conc. = 20.8 µM against same cell 
HO lines
O
HO
H
Corosolic acid, 125
Triterpene 1.32
H
OH
HO
O O
O
HO
Jacoumaric acid, 126
Cystoseira baccata Diterpenoids 20.4 L. infantum Non-toxic up to [134]
(Marine) (promastig- 126.6
 O otes)
O
O O
OH
Tetraprenyltoluquinone, 127
O
Diterpenoids 44.5 84.5
O
OH O
OH
Tetraprenyltoluquinol, 128
1 3
The search for putative hits in combating leishmaniasis 527
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Pseudelephanto- Sesquiterpene 0.06 L. infantum 1.47 ± 0.08 [135]
pus spiralis lactone (promastig- 0.97 ± 0.07
otes) 5.57 ± 1.9
O O L. infantum HO O (amastigotes)
L. infantum
HO (promastig-O O otes)L. infantum
O (promastig-
O otes)
L. infantum
Diacetylpiptocarphol, 129 (amastigotes)
O O 0.012O
HO
Sesquiterpene 0.02
O lactone
HO
O
O
O 0.005
Piptocarphin A, 130
Sesquiterpene 0.244
lactone
O O O 0.048
HO
O
HO
OH
O
Piptocarphins D, 131
1 3
5 28 P. O. Sakyi et al.
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Nectria pseudotri- Sesquiterpene 0.092 L. infantum 3.17 ± 1.0 [136]
chia Lactone (promastig-
O O O otes)
HO 0.023 L. infantum
O (amastigotes)
HO
OH
[(2Z)-8,10,11-trihydroxy-1,10-dimethyl-5-oxo-
4,14-dioxatricyclo[9.2.1.03,7]tetradeca-2,6-
dien-6-yl]methyl acetate, 132
Highly selective to 
HO parasites compared to 
O O Sesquiterpenoid 0.063 L. braziliensis VERO cells and THP-1 
O (amastigotes) (a human leukaemia O monocytic cell line). 
 All > 200 µM.
OH
O
10-acetyl trichoderonic acid A, 133
O
O
Monoterpene 0.104
OH
O
O OH
6'-acetoxy-piliformic acid, 134
Monoterpene 0.117
OH
O
O OH
5',6'-dehydropiliformic acid, 135
O
OH
OH Monoterpene 0.37
O
Piliformic acid,136
1 3
The search for putative hits in combating leishmaniasis 529
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Croton echioides Diterpenoid 0.11 L.amanson- N.T [137]
O ensis
(promastig-
otes)
COOH
O O
Methyl-15,16-Epoxy-3,13(16),14-
Neo-Clerodatrien-17,18-Dicarboxylate, 137
O
Diterpenoid 0.027
COOCH3
O O
Nasimalun B, 138
O O Diterpenoid 0.025
H
O
Hardwickiic acid methyl ester, 139
 
Taxodium disti- Diterpenoid 2.5 L. donovani High toxicity against [138]
chum OH (promastig- HT-29 colorectal 
otes) carcinoma cells
O
H 0.52 L. amazon-
ensis
OO
O
Taxotrione, 140
 
1 3
5 30 P. O. Sakyi et al.
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Lippia sidoides Monoterpene 23.9 L. amazon- 36.5 µM [139]
ensis >100 µM
(Promastig- 63.6 µM
otes)
HO
Thymol, 141
OH O
Monoterpene 11.0
Acetyl-Thymol, 142
OH O
Monoterpene 15.1
Benzoyl-Thymol, 143
 
Trixis antimenor- 0.3 L. amazon- N. T [97]
rhoea HO ensis
(promastigote)
Sesquiterpene 0.96 L. brazilensis
O (promastigote)
O O O
OO
O
O
O
Trixanolide, 144
 
Bifurcaria bifurc- OH Diterpene 18.8 L.donovani Toxicity potential [140]
ata against L6 primary 
(Marine) OH OH myoblast cell was 
observed at 56.6 µM
Bifurcatriol, 145  
1 3
The search for putative hits in combating leishmaniasis 531
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Dictyota spiralis Diterpene 15.47 L. amazon- 23.4 [141]
(Marine) ensis 69
(promastigote)
H CO L. amazon-3 ensis
(promastigote)
HO
spiralyde A, 146
O Diterpene 36.81
H
3,4-epoxy-7,18-dolabelladiene, 147
 
Stypopodium O OH Diterpene 9 L. amazon- 8.4 μM [142]
zonale ensis
(Marine) (amastigotes)
H
O
OH
Atomaric acid,148  
1 3
 532 P. O. Sakyi et al.
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Plumarella deli- O L. donovani Cytotoxicity potential 
catissima (amastigotes) against human lung 
(Marine) O O carcinoma, cells 
Diterpene 0.025 exhibited low toxic 
O OO H
O potentials which 
were
O H >50
O
Keikipukalide B, 149
O Diterpene 0.026 >50
O
O OO H
O H
O
Keikipukalide C, 150
Diterpene 0.034 >50
O
O O
HOH OO
O H
O
Keikipukalide D, 151
O
Diterpene 0.022 >50
O O H
O O
O
H
O
Keikipukalide
E,152
O Diterpene 1.9 >50
O
H
O
O
H
O
Pukalide aldehyde, 153
O O H
H H Diterpene 4.4 >50
H
H
H O
O H O
Ineleganolide, 154  
1 3
The search for putative hits in combating leishmaniasis 533
Table 3  (continued)
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Laurencia viridis Br Diterpene 8.36 L. amazonen- [143]
(Marine) H sis (Promas- 0.22
HO O tigote)OH O 28.26 L. donovani
O (promastig-
O otes)
Dehydrothyrsiferol, 155
Br
H Diterpene 7.00 L. amazonen- 4.6
O
OH O sis (Promas-tigote)
O
O 18 L. donovani(promastig-
HO otes)Lubol, 156
Br
H Diterpene 34.65 0.6
HO OOH O
O
HO O
22-hydroxydehydrothyrsiferol, 157
Br
H Diterpene 12.96 1.4
O
O
HO
O OO
Saiyacenols A, 158
Br
H Diterpene 10.32 >100
O
O
HO
O OO
Saiyacenols B, 159  
1 3
 534 P. O. Sakyi et al.
Natural product Chemical structure Class of natural IC50/μg/mL Organism Toxicology References
source product tested
Dysidea avara 28.21 L. infantum Low toxicity against [144]
(Marine) (Promastig- human microvascu-
otes) lar endothelial cells 
Sesquiterpene 20.28 L. tropica and (human acute 
(Promastig- monocytic leukemia 
otes) cells with CC50 
H 7.64 L. infantum 62.19 and > 100 
O (Amastigote) respectively.
O
Avarone, 160
7.42 L. infantum 36.8
(Promastig-
Sesquiterpene otes)
7.08 L. tropica 31.75
H (Promastig-
O otes)
3.19 L. infantum
(Amastigote)
O
Avarol, 161
 
membered ring. Ergosterol, the main sterol in Leishmania 
parasite constitute a major component of the cell membrane the control of pro-inflammatory cytokines by anti-inflamma-
and mitochondrion of the parasite which when inhibited tory counterparts [150]. 182 halted the process of electron 
leads to parasite death. 164 extracted from Trametes versi- transport and ATP generation in the mitochondria [151]. In 
color mimics Leishmania ergosterol due to similarities in addition, plasma membrane alterations with the administra-
core structure but a break in oxygen–oxygen bond in ergos- tion of the other isolates depicts a sterol metabolism inhibi-
terol peroxide unleashes oxidation on lipids, proteins and tion as a contributing factor to parasite death [151].
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 dele- 2  Conclusion
terious effects of other lanostane type steroids on membrane 
state and integrity causing parasite death has been reported Though humans and natural products did not co-evolve, 
[146, 147]. Also, anti-infective studies of Sassafras albi- chemical prototypes from natural origins have numerous 
dum and its bioactivity guided fractionation reported a sterol targets in both human and animal diseases. Their structural 
and fatty alcohol, 162 and 163 respectively [36] as prom- diversity, large hemical space and safety are intriguing char-
ising antileishmanial compounds. 162 which differs from acteristics that makes them very attractive. Diverse biomo-
cholesterol at C24 position is believed to kill the parasite lecular functions including anti-leishmanial potentials are 
via an apoptosis mechanism involving DNA fragmentation, possessed by various plant families including Fabaceae, 
inhibition of inflammation cytokines and the activation of Annonaceae, Euphorbiaceae, Rutaceae, Myrsinaceae, 
caspases [148, 149]. Evaluating the suicidal action of active Liliaceae, Araliaceae and Simaroubaceae, as well as endo-
isolates from Pentalinon andrieuxii, 181 induced changes phytes genera Alternaria, Arthrinium, Penicillium, Cochloi-
in immune responses particularly via necrosis and apoptosis bus, Fusarium, Colletotrichum, and Gibberella, and marine 
characterized by increase in IL2 and IFN-γ which insinuates natural product possess.
1 3
The search for putative hits in combating leishmaniasis 535
Table 4  Various classes of steroids, fatty alcohol, lignan, and butanolide with their  IC50 exhibiting antileishmanial properties
Natural product Chemical structure IC50 Organism Toxicity References
source tested
Sassafras albi- Steroid 54.3 L. amazon- Nontoxic against [36]
dum ensis BALB/c mouse 
(Promastig- macrophages 
ote) up to
182
H
H H
HO
Beta-Sitosterol, 162
Fatty 19.9 157
alcohol
1-Triacontanol, 163
HO  
Trametes versi- L. amazon- Toxicity profile [152]
color ensis against 
Steroid (Amastigote) peritoneal 
H macrophages
HO OO H
1.70 42.9 μM
Ergosterol peroxide, 164
O
Steroid 0.07 39.4 μM
HO
HO
H
Trametenolic acid B, 165  
1 3
5 36 P. O. Sakyi et al.
Table 4  (continued)
Natural product Chemical structure IC50 Organism Toxicity References
source tested
Aspergillus ter- Steroid 11.2 L. donovani N. T [153]
reus
H
H
HO
(22E,24R)-stigmasta-5,7,22-trien-3-ol, 166
Steroid 15.3
H
H H
O
Stigmast-4-ene-3-one, 167
Steroid 54.3
H
O
Stigmasta-4,6,8(14),22-tetraen-3-one, 168
HO
O Bute- 7.27
nolide
O
O
OH
O
O
Terrenolide S, 169  
1 3
The search for putative hits in combating leishmaniasis 537
Table 4  (continued)
Natural product Chemical structure IC50 Organism Toxicity References
source tested
Solanum sisym- OH Steroid 6.60 L. amazon- N.T [127]
briifolium HO ensis
HO OH 3.10 L. brazilen-
sis
O
O
OH
OHH
H H
HO
Cilistol A, 170
HO
O > 100 L. amazon- N. T
O H O Steroid ensis
H H
OH 59.8 L. brazilen-
sis
OH
OH
Cilistadiol, 171  
Paecilomyces 18.2 L. ama- Non-toxic up [154]
sp. OH zonensis to 183 µM 
(Marine) O (Intra- in mouse 
Amastig- peritoneal 
O ote) macrophage.
Harzialactone, 172 L. amazon-
ensis
O
7.89
OH
O
3-(3,7-dimethyl-2,6-octadienyl)-
4-methoxybenzoic acid, 173
 
1 3
 538 P. O. Sakyi et al.
Table 4  (continued)
Natural product Chemical structure IC50 Organism Toxicity References
source tested
Musa paradi- Steroid 201 L. infantum Low toxicity [155]
siaca (Amastigote) profiles against 
mammalian 
raw cell lines
462 µM
O
31-Norcyclolaudenone, 174
Steroid 185 569 µM
H
O
H
Cycloeucalenone, 175
Steroid 127 1147 µM
HO
H
24-Methylene-cycloartanol, 176
Steroid 98.5 150 µM
H
H H
HO
Stigmasterol, 177
+
H
H H
HO
Sitosterol, 178  
1 3
The search for putative hits in combating leishmaniasis 539
Table 4  (continued)
Natural product Chemical structure IC50 Organism Toxicity References
source tested
Pentalinon 0.08 L. mexicana [150]
andrieuxi (promastig-
otes)
Steroid 0.009 L. mexicana
(amastig-
otes)
H
H H
O
Cholestra-4,20,24-trien-3-one,179
O
OH
H Steroid 0.03
H H 0.004
O
6,7-Dihydroneridienone, 180
 
H Steroid 0.06
H H 0.009
O
24-Methylcholesta-4,24(28)-dien-3-one, 181
1 3
5 40 P. O. Sakyi et al.
Table 4  (continued)
Natural product Chemical structure IC50 Organism Toxicity References
source tested
Porophyllum S Terthio- 37 L. amanzon- CC50 = 370 μg/ [151]
ruderale phene ensis mL
S (amastig-
otes)
S
5-methyl-2,2:5,2-terthiophene,182
O
51 CC50 = 335 μg/
mL
O
C
S S
5-methyl-[5-(4-acetoxy-1-butynyl)]-
2,2-bi-thiophene, 183  
Marine Cyano- OH Mac- 4.67 µM L. donovani N.T [156]
bacteria rolide (amastig-
(Marine) otes)
HO
OH
O O HO
OH
HO OH
OH
Palstimolide, 184  
Management of leishmaniasis is plagued with systemic arginase inhibition, topoisomerase II intercalation, suppress-
toxicity, high cost of existing drugs, lengthy treatment ing NF-κB expression and other pro-inflammatory, and tryp-
periods, drug resistance and parasite diversity. Different anothione reductase inhibition.
classes of natural products such as alkaloids, terpenes, ter-
penoids, and phenolics are examples of compounds evalu- Author contributions POS, RKA and SKK initiated the work, POS 
ated towards the treatment of leishmaniasis. They exert wrote the first draft supervised by SKK and POS All the authors con-tributed to the writing of the review, read and accepted the final draft 
their antileishmanial activities through calcium channel article.
inhibitors, immunomodulatory through the enhancement of 
NO in macrophages, alterations in organelle membranes of Declarations 
the endoplasmic reticulum, respiration incapacitation and 
apoptosis. Other antileishmanial related mechanisms include Conflict of interest The authors declare no conflict of interest.
cell membrane disruption via sterol biosynthesis inhibition, 
reactive oxygen species (ROS) generation, iron chelation, Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, 
1 3
The search for putative hits in combating leishmaniasis 541
adaptation, distribution and reproduction in any medium or format,  27. T.J. Gintjee, M.A. Donnelley, G.R. Thompson, J. Fungi 6, 28 
as long as you give appropriate credit to the original author(s) and the (2020)
source, provide a link to the Creative Commons licence, and indicate  28. S.T. De Macedo-Silva, J.A. Urbina, W. De Souza, J.C.F. Rodri-
if changes were made. The images or other third party material in this gues, PLoS ONE 8, (2013)
article are included in the article’s Creative Commons licence, unless  29. B.B. Mishra, V.K. Tiwari, Eur. J. Med. Chem. 46, 4769 (2011)
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use, you will need to obtain permission directly from the copyright Natural Products from Plants, 1st ed. (Elsevier B.V., 2012)
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Affiliations
Patrick O. Sakyi1,2 · Richard K. Amewu1 · Robert N. O. A. Devine2 · Emahi Ismaila2 · Whelton A. Miller3,4,5 · 
Samuel K. Kwofie6,7 
 Patrick O. Sakyi 3 Department of Medicine, Loyola University Medical Center, 
 patrick.sakyi@uenr.edu.gh; opsakyi@st.ug.edu.gh Maywood, IL 60153, USA
 Richard K. Amewu 4 Department of Molecular Pharmacology and Neuroscience, 
 ramewu@ug.edu.gh Loyola University Medical Center, Maywood, IL 60153, 
 Robert N. O. A. Devine USA
 robert.devine.stu@uenr.edu.gh 5 Department of Chemical and Biomolecular Engineering, 
 Emahi Ismaila School of Engineering and Applied Science, University 
 Ismaila.emahi@uenr.edu.gh of Pennsylvania, Philadelphia, PA 19104, USA
6
 Whelton A. Miller  Department of Biomedical Engineering, School 
 wmiller6@luc.edu of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, PMB LG 77, Legon, Accra, 
1 Department of Chemistry, School of Physical Ghana
and Mathematical Sciences, College of Basic and Applied 7 Department of Biochemistry, Cell and Molecular Biology, 
Sciences, University of Ghana, P. O. BOX LG 56, Legon, West African Centre for Cell Biology of Infectious 
Accra, Ghana Pathogens, College of Basic and Applied Sciences, 
2 Department of Chemical Sciences, School of Sciences, University of Ghana, P.O. Box LG 54, Accra, Ghana
University of Energy and Natural Resources, Box 214, 
Sunyani, Ghana
1 3