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Biomarkers as Targeted Herbal Drug Discovery
between two phases, namely promastigote phase and amastigote phase
(Figure 5.2a). The promastigote is originated in the midgut of sand-fly and
the amastigote mostly exists in humans (macrophages) and other vertebrate
congregations (Roy et al., 2010; Ladurner et al., 2000). As the sand-fly slurps
the amastigote infested blood from the host, these amastigote gets converted
into promastigotes form within 5 hours of incorporation in the inner part of
the gut of insect. Within a period of 24–48 hours, the amastigotes wholly get
converted into active and motile promastigotes by the procedure of binary
separation. In a time period of 7–10 days of consumption of disease-ridden
blood the promastigotes get carried to the mid-gut of sand-flies and once this
infected sand-fly bites a new host, it gets infected with promastigote. Further,
this causes fast penetration of neutrophils and macrophages existing at the
site of bite, where the promastigote tends to become immobile and transforms
rearer to amastigote form (Figure 5.2b). These amastigotes penetrate and
take shelter in the active cells of RES (place where they endure proliferation
by binary fusion). Finally, when this developed RES cells get shattered, it
primes to deliverance of 40–160 amastigotes and causes interruption of the
immunity as the T-helper cell type 1 gets diminished (Kaye and Scott, 2000).
Taxonomical classification of Leishmania parasite.
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(a) The life cycle of Leishmania parasites and (b) Involvement of multiple cell
types in the uptake of Leishmania parasites.
Source: Reprinted with permission from Kaye and Scott (2011). © Springer Nature.
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Biomarkers as Targeted Herbal Drug Discovery
The drugs comprising antimony (pentavalent antimonials) as a principal
component are primarily the drugs of choice as anti-leishmanial drugs
(ALD) for first line cure of Leishmaniasis where confrontation has not
been stated (Singh et al., 2006). These comprise of the generic sodium
stibogluconate (pentostam, Figure 5.3), the branded meglumine antimoniate, which is been in practice for over five decades. Unfortunately, the
Leishmania protozoal parasites have been progressively developed the
resistance to these pentavalent antimonial drugs and hence this raised
a question for their usage in disease-endemic extents (Maltezou, 2010).
Since, these antimonials are directed intravenously (I.V) or intramuscularly (I.M), they are not suitable for patients. They are also concomitant
with adverse reactions, which include biochemical pancreatitis, elevation
in serum aminotransferases level, and electro-cardiographic oddities
(Polonio and Efferth, 2010).
Additionally, second-line ALD consists of amphotericin B (AmP B)
(Figure 5.3), particularly used in extents where antimonial resistance is
communal (Bern et al., 2006). It displays strong conjugation to ergosterol,
the chief sterol of leishmanial and fungal cell membranes. Disappointingly, AmP B is toxic (Hassane et al., 2001; Laborin and Vargas, 2009)
despite its high efcacy. Other preparations of AmP B have principally
evaded the adverse effects although some are prominently expensive
(Singh and Singh, 2012). Other second-line antileishmanial chemotherapeutics contain miltefosine (Figure 5.3), initially established as anticancer
molecules. It was the earliest orally administered drug molecule for cure
of VL. Having proved its notable efciency in clinical trials (Sundar,
2006; Bhattacharya et al., 2007), it was reected as a major discovery
in antileishmanial chemotherapy (Jha et al., 1999; Sundar et al., 2006).
However, severe apprehensions of its teratogenicity and its long halflife (152 h), which further may boost the appearance of drug resistance,
limited its usage (Sundar et al., 2011). Paromomycin (Figure 5.3), alterna-
tive second line ALD, cures both VL and CL although its insufciency
has hindered its usage in prevalent regions (Thakur et al., 2000; Thakur,
2003). Sitamaquine (Figure 5.3), the only ALD initially developed to cure
VL, provides a benet for oral administration. Its efciency and permissibility was conrmed in a phase II clinical experimental in India (Jha
et al., 2003). Its potency has also been conveyed in a Kenyan research
clinical trial. However, adverse effects like cyanosis, vomiting, dyspepsia,
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glomerulonephritis, nephritic syndrome, headache, abdominal pain, and
kidney dysfunctioning were witnessed in both the clinical trials (Wasunna
et al., 2005). Pentamidine (Figure 5.3) is been used to cure antimonial-
stubborn VL patients although its deteriorating efciency has led to its
usage (Das et al., 2001).
Presently used anti-leishmanial drugs.
The present-day encounters allied with present chemotherapeutic interferences for Leishmaniasis permit rigorous research determinations into
unique antileishmanial treatments and therapies. In this segment, we have
reviewed for the natural products that have confirmed marked ALA. The
ALA of numerous unpolished extracts and parts isolated from plant sources
has been accredited to the compounds fitting to varied chemical clusters,
which includes terpenoids (monoterpenes, diterpenoids, triterpenes,
sesquiterpenes,), phenolic complexes (e.g., flavonols, aurones, chalcones,
lignans, quinines, coumarins, tannins), and alkaloidal complex metabolites
(indole alkaloids, quinoline alkaloids, isoquinoline alkaloids) (Salem and
Werbovetz, 2006).
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Biomarkers as Targeted Herbal Drug Discovery
Fournet et al. (1993) demonstrated the actions of some selective quinolone
alkaloids isolated from Galipea longiflora (Rutaceae) and evaluated their
ALA in BALB/c mice diseased with L. venezuelensis or L. amazonensis;
strains causing CL. The pharmacokinetic in vitro and animal model-based
in vivo studies revealed that: two 3-carbon series quinolones: chimanine D
and 2-n-propylquinoline, earlier one was found to be more effective than
N-methylglucamine (NMG) antimonate beside L. amazonensis. Further, 5
more quinoline alkaloids [2- (3,4-methylenedioxyphenylethyl) quinoline,
cusparine, 2- (3,4-dimethoxyphenylethyl) quinoline, chimanine, and skimmianine, were found to be active as that of conventional drug. These active
quinolone alkaloids containing derivatives showed no deceptive toxicities
throughout the experiment. Bringmann et al. (2000) isolated two new bioactive alkaloids, ancistroealaines A and B and three naphthoic acid derivatives,
eleutherolic acid and ancistronaphthoic acids A and B respectively, from
Ancistrocla dusealaensis (Ancistrocladaceae). Further in vitro results showed
that ancistroealaines A exhibited IC
(µg/mL) values of 4.1 and 2.35 against
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L. donovani and T. cruzi, respectively. Further, Bringmann et al. (2003)
isolated a novel naphthylisoquinoline alkaloid, ancistrolikokine D, and likewise 5,80-attached alkaloid ancistroealaine A, further two biosynthetically
allied, cis-isoshinanolone, and ancistronaphthoic acid B, from Ancistrocladus
likoko J. Leonard (Ancistrocladaceae). The compounds showed ALA against
L. donovani, T. cruzi, and T. brucei rhodesiense. Muhammad et al. (2003)
Psychotriaklugii (Rubiaceae) conceded two novel klugine, benzoquino-
lizidine alkaloids and 7-O-demethylisocephaeline, collected with earlier
known isocephaeline (ICP), cephaeline (CPL) and 7-O-methylipecoside.
CPL confirmed effective in vitro ALA alongside L. donovani (IC
50
0.03
µg/mL) and was more effective as compared to pentamidine and AmP B,
correspondingly, while klugine (IC
seem to be less potent (<13- and <15-fold) than CPL. Further, emetine (IC
0.40 µg/mL) and ICP (IC50 0.45 µg/mL)
50
50
0.03 µg/mL) was as effective as of CPL, but was >12-fold more toxic than
CPL against VERO cells (IC
0.42 vs. 5.3 µg/mL). Klugine and CPL also
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displayed strong antimalarial activity (AMA) against P. falciparum. Bring-
mann et al. (2004) isolated three novel naphthylisoquinoline alkaloids; all of
the three compounds were S-aligned at position C-3 and endure oxygen at
position C-6. Further, in vitro studies exhibited their anti-pathogenic activity
against leishmaniasis, Chagas’ disease, malaria, and African sleeping sickness. Reina et al. (2014) isolated 23 indole alkaloids from various parts of
Aspidosperma desmanthum and A. spruceanum. Further, the antiparasitic
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activity of these isolated composites experimented against T. cruzi and L.
infantum and their non-précised cytotoxicity on the particular mammalian
cells. Larghi et al. (2015) reviewed the present facts about the assortment of
the biological actions linked to neocryptolepine (NCL), its correspondents
and byproducts. Remarkably, NCL showed weak ALA against L. donovani,
with IC50 49.5 ± 3.7 µM, nearly two orders of magnitude greater than the
standard miltefosine (IC
0.56 ± 0.07 µM). NCL and other quinoline alka-
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loids have shown notable docking to LmajMetRS, a protein from L. major.
Kolodziej et al. (2001) tested the immunomodulatory effect and antiparasitic effect (against intra- and extra-cellular promastigotes) for a series of
27 hydrolyzable tannins and related compounds. Furthermore, of these all
compounds, Gallic acid (GAE) and its methyl ester induced murine macrophages. The in vitro studies revealed that, tumor necrosis factor-α (TNF-α)
inducing potential of examined polyphenols, was found to be highest in
oligomeric ellagitannins, and potent interferon (IFN)-like activity was
found highest in some ellagitannins and majority of dehydroellegitannins.
Furthermore, all polyphenols showed pronounced ALA against L. donovani,
including possibilities for tempting the release of NO, TNF-α and IFN-like
actions in macrophage-like cells. Cortez et al. (2016) evaluated the cytotoxicity, ALA, and curative potential of Arrabidaea chica. Further, results
stated that the dried extracts confined of flavonoids, tannins metabolites,
anthocyanidins complexes, and chalcones. Moreover, the ALA of A. chica
produced acceptable outcomes in concentrations range of 60–155.9 μg/mL.
Cytotoxic assay exposed a 50% decrease in viable cells at an amount of
189.9 μg/mL.
Sairafianpour et al. (2001) isolated cryptotanshinone (quinoid diterpene),
and 3 novel natural products, 1-oxocryptotanshinone, 1α-hydroxycryptotan-
shinone and 1-oxomiltirone extracted from the roots of Perovskia abrotanoides (Lamiaceae). These composites exhibited ALA in vitro (IC
mM) which was further used for the management of CL. The isolated
terpenes are trained in the development of erudite malarial parasites, drugsensitive KB-3-1 human carcinoma cell line, multidrug-resilient KB-V1
18–47
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Biomarkers as Targeted Herbal Drug Discovery
cell line, and human lymphocytes triggered with phytohaemagglutinin A
(IC
5–45 mM). Tiuman et al. (2005) investigated the in vitro ALA of PTL,
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refined from the hydro-alcoholic extract of varied plant parts of Tanacetum
parthenium, against L. amazonensis. PTL showed substantial activity
against the promastigote phases of L. amazonensis (IC
0.37 µg/mL). Foki-
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alakis et al. (2006) evaluated the ALA of 11 cis-clerodane type diterpenes,
7 labdane oriented diterpene and triterpene, extracted through Cistus
monspeliensis (Cistaceae), against L. donovani promastigotes. The selec-
tive isolated compounds exhibited ALA (IC
3.3 m g/mL, 3.4 m g/mL and
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3.5 m g/mL, respectively). Barrera et al. (2008) evaluated the consequence
of three plant-derived sesquiterpene complexed lactones, from cultured L.
mexicana promastigotes. Results displayed that the composites suppressed
the in vitro development of the selected parasites at moderately lower
concentrations, further the effect was fast and irreversible (IC
2–4 µM).
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Furthermore, these composites showed lesser cytotoxicity for the mammalian cells. All the three lactones persuaded DNA fragmentation and the
aptitude of parasites to attack the Vero cells was reduced by acquaintance to
lower concentrations of these composites. Karioti et al. (2009) assessed the
ALA of three irregulars, linear sesquiterpene modulated lactones freshly
isolated from Anthemis auriculata, against T. brucei rhodesiense and T.
cruzi, also for xenic amastigotes of L. donovani. The cytotoxic efficiency of
these compounds was also evaluated alongside mammalian (rat) skeletal
myoblasts (L6 cells). All composites presented strong trypanocidal and
ALA. All the three extracts influenced toxicity on mammalian cells; further,
this helped to limit their usage as antiprotozoal agents. Maregesi et al.
(2010) identified the putative active constituents of Elaeodendron schlech-
teranum (Celastraceae). Bioassay-directed sequestration managed to
empathy of tingenin B; chief antibacterial integrals. Moreover, this
compound was found to be vigorous beside B. cereus, S. aureus and E. coli
< 0.25 µg/mL). Furthermore, antiparasitic action was detected against
(IC
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T. cruzi (IC
< 0.25 µg/mL), T. brucei (<0.25 µg/mL), L. infantum (0.51 µg/
50
mL), and P. falciparum (0.36 µg/mL). Tingenin B was extremely cytotoxic
to MRC-5 cells (CC
0.45 µg/mL), demonstrating a deprived selectivity.
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Misra et al. (2010) assessed the in vitro activity of terpenoid compounds,
isolated from Polyalthia longifolia, by means of intracellular transgenic
green luminescent protein firmly expressed L. donovani parasites. This
compound, a clerodane diterpenes, found to be potent as human DNA topoisomerase, introverted recombinant DNA topoisomerase I (TP-1), which
eventually persuaded apoptosis. Further, the molecular docking assays
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specified that five robust hydrogen-bonding interfaces and hydrophobic
interfaces of this complex with L. donovani DNA-TP-1 was accountable for
its ALA. Bharate et al. (2011) carried the quantitative structure-activity
relationship (QSAR) study, carrying out a sequence of phloroglucinolterpene adjuncts showing ALA to invent the essential characteristics which
was vital for the bio-chemical action. The QSAR study was conceded out
using J. Chem. for Excel and the finest QSAR model was imitated by
multiple regression examination. The finest model includes four products
shaped correlation coefficient of 0.930 (s = 0.096, F = 65.93, P <0.0001)
based on stepwise multiple regression technique. The study concluded,
lipophilic oddity (C Log P), Haray index, isoelectric point, and Platt index
played a significant role in ALA of these complexes. ALA of numerous
architecturally alike naturally arising euglobals was also prophesied using
developed QSAR model. Sidana et al. (2012) quarantined the terpenoidal
ingredients by isolating the dried extracts using chloroform-methanol
mixture of dried leaves of Eucalyptus loxophleba for evaluation of ALA
against the L. donovani promastigotes by means of an Alamar blue assay.
Further, results disclosed that 3-acetyl loxanic acid and loxanic acid collectively exhibited ALA (IC
133–235 μM) in contradiction of the promasti-
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gotes of established strain. Moura do Carmo et al. (2012) analyzed the
production of essential oils (EOs) gained from the leaves of Piper demer-
aranum and Piper duckeiby GC-MS technique. The chief constituents found
in P. demeraranumoil: limonene, β-elemene and in P. duckei oil: germacrene
D, trans-caryophyllene. P. duckei and P. demeraranum oils showed potential
biological action (IC
15–76 μg mL–1) against L. amazonensis, and hence
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these EO extracts could be used in the treatment of CL. Tiuman et al. (2014)
established the fact that parthenolide (PTN) induced cell death in amastigote
forms of L. amazonensis. Further, results specified that the ALA of PTN
was associated with autophagic vacuole advent, lessening of flexibility,
forfeiture of membrane veracity and mitochondrial dysfunction. Rottini et
al. (2015) assessed the inhibitory effect of (–) α-bisabolol, in contradiction
of promastigotes and amastigotes phases of L. amazonensis, caused alterations in cytotoxicity of the treated cells. This compound revealed an important ALA against promastigotes (IC
4.26–8.07 μg/mL). Approximately
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around 69% of the promastigotes phases agonized mitochondrial membrane
injury after the treatment with this compound, signifying inhibition of the
metabolic action of the parasites. Teles et al. (2015) isolated 3β,6β,16β-
trihydroxylup-20 (29)-ene from Combretum leprosum fruit, assayed for
anticancer effects. It showed substantial activity in contradiction to the
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Biomarkers as Targeted Herbal Drug Discovery
intracellular amastigotes of L. (L.) amazonensis. Results indicated that the
metabolite inhibits L. (L.) amazonensis amastigote duplication and existence inside the host cells and bioinformatics studies intensely indicated
this molecule to be an impending inhibitor of topoisomerase IB. Bufalo et
al. (2016) isolated 4 diterpenes from Salvia deserta extracted roots. Taxodione was imitated leishmanicidal (IC
46 μM-0.46 mg/L) against L.
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donovani and showed antifungal and antimicrobial actions. The crude
extract section, containing the isolated compounds, exhibited stouter antibacterial activity (1.3 mg/L for S. aureus and 1.1 mg/L for methicillin-
resilient S. aureus). Garcia et al. (2017) evaluated the ALA of Citrus sinensis
(L.) (Rutaceae) extracts. Further, results of the extracts exhibited ALA (IC
50
25.91 ± 4.87). Additionally, 60 µg/mL of sample extract abridged the
amount of intracellular amastigotes and the ratio of diseased macrophages
in 62% and 37%, respectively. Ulloa et al. (2017) assessed the ALA of
enhydrin, uvedalin, and polymatin B, isolated from Smallanthus sonchifo-
lius, against L. Mexicana and T. cruzi. Further, results showed that the three
compounds unveiled ALA (IC
0.42–0. 54 and 0.85–1.64 μg/mL for
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promastigotes and amastigotes respectively. Want et al. (2017) prepared
nanoliposomal artemisinin (ARM), a sesquiterpene lactone, (NLA) using
thin-film hydration technique and optimized the formulation by using BoxBehnken design (BBD) with a mean globule size (83 ± 16 nm), PDI (0.2 ±
0.03), zeta potential (–27.4 ± 5.7 mV), and drug loading (DL) (33.2% ±
2.1%). NLA expressively defamed the intracellular infection of L. donovani
amastigotes and quantity of infected macrophages (IC
6.1 ± 1.4 μg/mL
50
and 5.2 ± 0.9 μg/mL, respectively). Rodrigues et al. (2018) evaluated the
ALA of Copaifera spp. oleoresins, the impact of crude dried extracts and
parts of oleoresin of samples through Copaifera paupera onto parasites: L.
infantum and L. amazonensis. Further, oleoresin comprising of α-copaene
(38.8%) showed the best action against L. amazonensis (IC
and against L. infantum (IC
= 65.9μg/mL). To upsurge the ALA, nano-
50
= 62.5 μg/mL)
50
emulsion encompassing copaiba oleoresin and α-copaene were established
and examined against L. amazonensis and L. infantum promastigotes, which
was further showed high ALA. Armah et al. (2018) apprised the ALA of
crude plant extract, its portions, and isolated complexes of E. ivorense by
means of direct totaling assay of promastigotes of L donovani using AmP B
as positive control. Further, a suggestively active methanol fraction (IC
2.97 μg/mL) related to AmP B (IC
2.40 ± 0.67 μg/mL). The unique diter-
50
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pene complexes extracted showed weak activity. Further, the results
presented additional aspect where these composites and their comparative
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profusions could act as chemotaxonomical bio-markers of the significant
genus.
Akendengue et al. (2002) isolated klaivanolide (KVL), from the stems of
Uvaria klaineana (Annonaceae). KVL showed persuasive in vitro ALA
against both sensitive and AmP B-impervious promastigote forms of L.
donovani (IC
1.75 and 3.12 mM, respectively). The molecule also exhibited
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in vitro trypanocidal activity (TPA) contrary to trypomastigote forms of T.
brucei. Tiuman et al. (2014) investigated the in vitro ALA of PTN against L.
amazonensis. PTN (lactone) refined from the extract of plant parts of Tanacetum parthenium exhibited substantial activity against the promastigote
form of L. amazonensis (IC
0.37 µg/mL). Barrera et al. (2008) assessed the
50
effects of some selective lactones, using cultured L. mexicana promastigotes
and further observed that the molecules originated from the plant extracts
exhibited strong ALA (IC
of 2–4 µM) as compared pure compound,
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ketoconazole. Karioti et al. (2009) estimated the in vitro ALA as well as
TPA activity of extracts, bearing lactones as chief components, against T.
bruceirhodesiense and T. cruzi. Results showed that Compound (2) appeared
to be the most active complex against all parasites, predominantly towards
T. bruceirhodesiense (IC50 0.56 mg/mL). Tiuman et al. (2005) confirmed
cell demise in amastigote phases of L. amazonensis induced lactone, PTN.
Further analysis and results indicated that the ALA of PTN was allied with
loss of membrane veracity and mitochondrial dysfunction. Ulloa et al.
(2017) estimated the activity of three selective lactones. Enhydrin, uvedalin,
and polymatin B, isolated from Smallanthus sonchifolius, on L. Mexicana
and T. cruzi. Further, the in vitro studies depicted that the three compounds
exhibited ALA (IC
0.42–0. 54 μg/mL).
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Sartorelli et al. (2007) analyzed the dried extracts and segments from the
fruits of Cassia fistula used for the treatment of VL. Hexane extract exhibited
substantial ALA beside the promastigote stage of L. chagasi. The bio-directed
degradation ensued in the seclusion of a sterol, clerosterol, further scrutinized in altered models. Promastigotes and intracellular amastigotes established high vulnerability (IC
10.03 μg/mL and 18.10 μg/mL, respectively).
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