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Plant derived therapeutics for the treatment of Leishmaniasis.

ARTICLE INFO

doi: 10.1016/j.phymed.2011.03.004

Keywords:

Antileishmanial

Amastigotes

Plant derived compounds

ABSTRACT

Diseases caused by insect borne trypanosomatid parasites are significant, yet remain a neglected public health problem. Leishmania, a unicellular protozoan parasite is the causative organism of Leishmaniasis and is transmitted by female phlebotamine sandflies affecting millions of people worldwide. In the wake of resistance to pentavalent antimonial drugs, new therapeutic alternatives are desirable. The plant kingdom has in the past provided several affordable compounds and this review aims to provide an overview of the current status of available leishmanicidal plant derived compounds that are effective singly or in combination with conventional anti-leishmanial drugs, yet are non toxic to mammalian host cells. Furthermore, delineation of the contributory biochemical mechanisms involved in mediating their effect would help develop new chemotherapeutic approaches.
Contents

Introduction                                     1056

Disease manifestations                           1057

Current therapeutic modalities of Leishmaniasis  1057

New alternatives in search                       1057

Mechanisms of action of plant derived compounds  1064

    Calcones                                     1064

    Flavnoids                                    1064

    Saponins                                     1064

    Quinone                                      1065

          Alkaloids                              1065

          Lingans                                1065

          Tannins                                1065

          Terpenoids                             1065

          Oxylipin                               1065

          Miscellaneous                          1065

Future perspectives                              1066

Conclusions                                      1066

Acknowledgements                                 1066

References                                       1066


Introduction

Leishmaniasis, a vector borne disease caused by an intra-macrophage protozoa. Leishmania (Order: Kinetoplastidae, Family: Trypanosomatidae, Genus: Leishmania) is generally transmitted by sandflies, either Phlebotomus (Old world) or Lutzomyia

(New World). Leishmania are among the most diverse of human pathogens, in terms of both geographical distribution and variety of clinical manifestations. The disease endemicity extends to over 88 countries, the major group (n = 72] belonging to the developing world while 13 belongs to the category of least developed countries; sadly, its public health impact remains grossly neglected. Globally, the population at risk is 350 million, overall prevalence being 12 million, 2 million new cases occur annually and the Disability Adjusted Life years (DALY) burden is considered to be 860,000 men and 1.2 million women (WHO 2007). The estimated annual incidence of visceral leishmaniasis (VL) is around 500,000 in 61 countries with 90% of these cases confined to 5 countries namely India (especially the state of Bihar and its adjoining states), Bangladesh, Nepal (Terai region), Sudan and North Eastern Brazil. With regard to the cutaneous form, 1.0-1.5 million cases are reported annually with 90% of the cases occurring in 8 countries, 6 being in the Old World (Afghanistan, Algeria, Iran, Iraq. Saudi Arabia, and Syria) and 2 in the New World (Brazil, Peru; WHO 2007; Jhingran et al. 2008).

The digenetic life cycle of the obligatory parasite. Leishmania consists of interlocking subcycles that includes spindle shaped flagellated promastigotes. occurring in the sandfly vector and oval shaped aflagellated amastigotes. dominating in the vertebrate host macrophages, and includes reptiles, rodents, canids, edentates, marsupials, equas, procynoids, ungulates and also primates (Bray 1974). The life cycle of Leishmania begins with a bite of the female sandfly which feeds on the vertebrate host and imbibes blood; once in the host, promastigotes are transformed into amastigotes within phagocytic cells. While in the mammalian system, amastigotes multiply such that phagocytic cells eventually rupture to further infect other cells, thus sustaining their survival. Leishmania have the capability to withstand, inhibit or circumvent the microbicidal activity of host macrophages, by subverting induction of both innate and adaptive immune responses by mediating an imbalance of T helper cells (Tripathi et al. 2007).Therefore the cure in all forms of Leishmaniasis is generally affected through upregulation of cellular immune responses capable of activating host macrophages and involves activation of Th1 cells that secrete IFN-[gamma], TNF-[alpha]. lL-2 along with other macrophage activating molecules.

Considering the intracellular localization of the pathogen, specific problems for antileishmanial drugs includes their ability to be internalized by host cells. Further confounding factors include rate of uptake, ability to resist intracellular degradation, intracellular trafficking, and possibility of host cytotoxicity. Therefore, when screening for leishmanicidal drugs, one needs to initially test in extracellular promastigotes which is technically easier and subsequently test the Identified promising compound(s) which also must have a high therapeutic index against intracellular amastigotes, a process that is technically more cumbersome.

Disease manifestations

There are over 20 species of Leishmania parasites causing a broad spectrum of signs and symptoms ranging from simple self healing skin ulcers caused by L major and other dermatropic species to more severe chronic mucocutaneous infections caused by L braziliensis and even severe life-threatening visceral leishmaniasis (VL) caused by the L donovani complex that includes L donovani and L infantum in the Old World while in the New World; the causative species is L chagasi.

Current therapeutic modalities of Leishmaniasis

WHO has enlisted Leishmaniasis to be eliminated by 2015 (WHO 2009), but in the absence of an effective vaccine, chemotherapy till date remains the most effective weapon in the therapeutic arsenal against Leishmaniasis (Murray et al. 2005). Treatment modalities are limited, as pentavalent antimonials which effectively served as the therapeutic mainstay against Leishmaniasis, have in recent years developed large scale resistance (up to 60% of treated cases of VL in India, especially in the state of Bihar). There are no clearcut answers for this localized focus of resistance, but a major contributory factor appears to be the poor socio-economic profile of these patients. In a study conducted by Sundar et al. (1994), a staggering 73% of patients with VL reported that they consulted unqualified practitioners, who in their humble ignorance inadvertently encouraged inappropriate use of the drug. In view of the toxicity of SSG, they administered low concentrations of drug, with a gradual step up and even prescribed drug free intervals. Understandably, all these practices exposed the parasites to 'drug pressure' leading to the parasite over a period of time to develop devious methods of drug evasion (Chakravarty and Sundar 2010)

Study of the mechanism(s) by which Leishmania spp. acquire resistance to antimony is a subject of intense research, and involves modulation of its influx, metabolism of antimony, thiol metabolism coupled with drug efflux. Studies using field resistant strains have shown downregulation of a transporter. Aquaglyceroporin 1 (Mandal et al. 2010; Maharjan et al. 2008). Furthermore, as antimonials mediate their anti-leishmanial activity via generation of oxidative stress, upregulation of the antioxidant pathways, e.g. non protein thiols protects parasites from antimony-mediated oxidative stress (Mandal et al. 2007). Furtheremore antimony resistant strains have demonstrated increased biosynthesis of trypanothione (a bis glutathionyl-spermidine conjugate, T[[SH].sub.2]), the major intracellular thiol of Leishmania parasites. This is accompanied by the amplification of GSH1 gene coding for [gamma]-glutamylcysteine synthetase and/or overexpression of ornithine decarboxylase, established rate limiting steps in synthesis of glutathione and spermidine, respectively (Mukherjee et al. 2007; Singh et al. 2007). Furthermore, an amplified T[[SH].sub.2] dependent antioxidant system especially Tryparedoxin peroxidase, also contributes by curtailing antimony-mediated production of reactive oxygen/nitrogen species (Wyllie et al. 2010). This increased formation of SbIII-thiol complexes (spontaneously or enzymatically) if accompanied with an enhanced extrusion, at a rate sufficient to outmatch the influx, helps to sustain antimonial resistance (Mandal et al. 2009).

Thus drug resistance in Leishmaniasis necessitates evaluation of alternative therapeutic modalities (Sundar and Chatterjee 2006; Gupta et al. 2010a) and include amphotericin B together with its liposomal formulations (Yardley and Croft 2000), paramomycin and sitamaquine. However, each has their attendant limitations of affordability, toxicity and also requires parenteral administration. Even the orally effective antileishmanial, Miltefosine is associated with gastrointestinal disturbances and teratogenicity with the potential to develop resistance (Sundar and Chatterjee 2006; den Boer et al. 2009).

New alternatives in search

Considering the present scenario, development and introduction of new antileishmanial compounds would indeed be welcome. A search is on for new drugs that are less toxic, easily available and within the reach of poor people most afflicted by the disease. In the ongoing search for better leishmanicidal compounds, plant-derived products are gaining ground being easily available and relatively cheap. Isolation and purification of active ingredients of medicinal plants was one the major forces that led to the birth of the pharmaceutical industry in the 19th century. After a long period of neglect, there has been a renewed interest in the analysis of "natural products" for the presence of inhibitors of enzymes essential for replication, cell cycle regulation or production of virulence factors. There are approximately 250,000 plant species worldwide of which only a fraction have so far been studied and they have shown potent chemotherapeutic properties (Kayser et al. 2003a; Salem and Werbovetz 2006). However, much remains to be explored to identify plants as sources of drugs especially as several plant metabolites have been shown to contain phytoconstituents with potent leishmanicidal activity. The Drugs for Neglected Diseases Initiative (DNDi) have an active screening programme for investigating natural products (http://www.dndi.org/).
Table 1
Antileishmanial activity of plant derived compounds as tested in vivo.

Plant compounds       Phytoconstituent/standard      Leishmania
                      drugs                          spp.
Chalcones
Chinese liquorice     Licochalcone A                 L. major
(roots)
                                                     L. donovani
                      Oxygenated chalcones           L. donovani
                      Pentostam
Piper aduncum         (i) 2',6'-Dihydroxv            L. am
(Piperaceae)          -4'-methoxy chalcones (DMC)    ozonensis
                      (ii) Encapsulated DMC
                      Glucantime
                      20 naturally occurring         L. donovani
                      chalcones
                      Amphotericin B
Psorothamnus polyden  (i) 2',4-Dihydroxy             L. donovani
ius                   -6'-methoxy-3', 5
                      -dimethylchalcone (ii) 2, 2,
                      4'-Trihydroxy -6'- methoxy-3,
                      5'-dimethylchalcone
                      (iii) Dalrubone (Benzopyran.   L. mexicana
                      red pigment) (iv)
                      Eriodictyol
Piper rusbyi          Chalcone flavokavain           L.
                                                     amazonensis
Flavonoids
Vitex negundo         Luteolin                       L. donovani
Fagopyrum esculentum  Quercetin                      L. donovani
(buck wheat)
Kalanchoe pinnata     Leaf extract                   L.
(Crassulaceae)                                       amazonenesis
                      K (P)                          L.
                                                     amazonenesis
                      Pentostam                      L.
                                                     amazonenesis
(2006b)
                                                     L. chagasi
(2006a.b)
                      (i) Quercetin, (ii) Quercetin  L.
                      3-O-[alpha]                    amazonenesis
                      -L-arabinopyranosyl (1 2)
                      [alpha] -L-rhamnopyranoside,
                      (iii) Quercetin (Quercetin
                      3-0 -L-rhamnopyranoside
Piper betle L.        EtOH extract                   L. donovani
                      MeOH extract (eugenol rich)    L. donovani
Tanacetum             Guaianolide                    L.
parathenium (L)                                      amazonensis
Schultz Bip
Bidens pilosa L.      Hydroalcoholic extracts        L.
(Asteraceae) and                                     amazonensis
Punica granatum L.
(Puniceae)
Saponins
Ivy Hedera helix      Hederagenin                    L infantum L
(Araliaceae)                                         tropica
Hedera colchika       [alpha] -Hederin [beta]-       L. mexicana
                      Hederin Hederacolchiside A1
                      Pentamidine Ampho B
Maesa balansae        Maesabalides III Maesabalides  L infantum
(Myrsinaceae)         IV
                      Amphotericin B                 L infantum
                      Stibogluconate
                      Stibogluconate                 L donovani
Pera benensis         Plumbagin                      L
                                                     amazonensis
                      3,3' - Biplumbagin
                      8,8'- Biplumbagin
                      Glucantime
Cephaelis             1-                             L.  donovani
camponutans           Acetylbenzoisochromanquinone
                      Pentostam                      L. donovani
Stephania dinklagei   N-Methyllirio dendronine       L. danovani
                      Sodium  stibogluconate         L. donovani
Helietta apiculata    Furoquinonline alkaloids and   L.
                                                     amazonensis
                      ND                             Ferreira et
                                                     al.
                      coumarins
                      N-Methlyglucamine              L. donovani
                      antimonate
Alkaloids
Enantia chlorantha    N-Methylteira                  L. donovani
                      hydroberberinium
(Annonaceae)          iodide                         L.
                                                     braziliensis
                                                     panamensis
                      Meglumine antimonate           L. donovani
Berberis aristata     Berberine Chloride             L. donovani
(Berberidaceae)
                      Pentamidine                    L. donovani
Ancistrocladus        Ancistroealaine A              L. donovani
ealaensis
                      Ancistroealaine B              L. donovani
                      Pentostam                      L. donovani
A. congolensis        Ancistrocongolines B           L. donovani
                      Andstrocongolines C            L. donovani
                      Pentostam                      L. donovani
                      6 naphthylisoquinoline
                      alkaloids
                      and a related benzopyranone
A. likoko             Ancistrolikokine D             L. donovani
                      Pentamidine
A. tanzaniensis                                      L. donovani
                      Ancistrotanzanine A
                      Ancistrotanzanine B
                      Ancistrocladidine
                      Miltefosine
A. griffithii                                        L. donovani
                      Ancistrogriffithine A
                      Ancistmgriffithine C
                      Pentostam
Leaves of Tabemae-    Superficial fluid of an EtOH   L.
                                                     amazonensis
montana               fraction (AF3)
catharinensis
Galipea               Quinoline alkaloids
longi-
flora
(Rutacea)
                      2- n-Propylquinoline           L.
                                                     amazonensis
                      Chinanine B                    L.
                                                     amazonensis
                      S[b.sup.v] (28 mg/kg)          L
                                                     amazonensis
                      Chinamine D                    L. donovani
Thamnosma             Rhodesiacridone                L. major
rhodesica
                      Amphotericin B                 L. major
Nuphar lutea          MeOH extract                   L. major
(Nymphaeaceae)
                      Paramomycin sulphate           L. major
                      Alkaloid fraction  (NUP)       L. major
Croton pullei var.    Julocrotine, a glutarimide     L.
                                                     amazonensis
glabrio               alkaloid
(Euphorbiaceae)
Indole alkaloids
Aurones               Aurone (6-hydroxy-2-           L. donovani
                      [phenylmethylene] -3(2H)-
                      benzofuranone)
Lignans
Haplophyllum          Diphyllin                      L.infantum
bucharic[micro]M
(Rutaceae)
                      Amphotericin B                 L. infantum
Tannins
                      Polyphenols,                   L. donovani
                      proanthocyanidins
                      Pentostam                      L. donovani
                      Amphotericin B                 L. donovani
Terpenoids
Monoterpenes
Leaves of Croton      Linalool                       L.
                                                     amazonensis
cajucura
(Euphorbiaceae)
Sesquiterpene
Artemisia annua       Artemisinin                    L. major
                                                     L donovani
                      Artemether                     L. major
Triterpenes
Betula sp.            Dihydrobetulinic acid          L. donovani
Pourouma              Ursolic acid                   L.
                                                     amazonenesis
guianensis
(Moraceae)
                      Oleanolic acid                 L.
                                                     amazonenesis
                      Meglumine antimoniate          L.
                                                     amazonenesis
Glycyrrhizza glabra   Water soluble                  L. donovani
L (Licorice)          18[beta]-glycyrrhetinic acid
                      (GRA)
Polyaithia            16                             L donovani
longifolia            [alpha]-Hydroxycleroda-3.13
(Annonaceae)          (14) Z-dien - 15. 16-olide
                      Miltefosine                    L. donovani
Oxylipin Tridax       Oxylipin (35)-16, 17           L. mexicana
procumbent            didehydrofalcarcinol
(Asceraceae)
                      Amphotericin B                 L. major
Momordica             Aqueous extract                L. donovani
                      Momordicartio                  L. donovani
Himatanthus sucuuba   (HsL)                          L.
Latex (Apocynaceae)                                  amazonensis
                      Glucantime                     L.
                                                     amazonensis
                      Amphotericin B                 L.
                                                     amazonensis
Tinospora sinensis    EtOH extract                   L.  donovani
                      Butanol fraction               L. donovani
                      Miltefosine                    L. donovani
Miscellaneous
Withania somnifera    MeOH extract                   L. donovani
(Aswagandha)
                      Withaferin A                   L. donovani
                      Amphotericin B                 L. donovani
Allium sativum L.     MeOH extract                   L. donovani
(Garlic)
                      G3                             L. donovani
Allium sativum L.     Ajoene                         L. mexicana
(Garlic)
Podolepsis hie        Gammapyrones                   L. donovanii
raciodes
(Asceraceae)
                                                     L. major
                                                     L. infantum
                                                     L. enriett
Zanthoxylum           Cantrtin 6-one                 L.
chiloperone var.                                     amazonensis
angustifolium
                      Meglumine antimonate           L.
                                                     amazonensis
Plant compounds       Phytoconstituent/standard      Leishmania
                      drugs                          spp.
Aloe vera             Leafy exudates                 L. donovani
(2007a,b, 2008)
                      SSG                            L. donovani
Chenopodium           Hydroalcoholic crude extract   L.
ambrosioides L.       (HCE)                          amazonensis
(Chenopodi- aceae)
                      Essential oils                 L.
                                                     amazonensis
Piper auritum         Essential oils                 L. donovani
                      Amphotericin B                 L. donovani
Physalis angulata     Physalins B                    L.
                                                     amazonensis
                      Physalins F                    L. major
Peganum harmala       Peganine hydrochloride         L. donovani
                      dehydrate
                      Miltefosine                    L. donovani
parasite removal in
hamsters
N. arbortristis L     Calceolarioside A (1)          L. donovani
(Night jasmine)
Sweria chirata        Amarogentin, a secoiridoid     L. donovani
                      glycoside
Ampelocera edentula   4-Hydroxy-1-tetralone          L.
                                                     amazonensis
Desmodium gangeticum  EtOH extract n-Butanol         L. donovani
                      fraction
                      -                              Singh et
                                                     al.(2005)
Quassia amara         Quassin                        L. donovani
Andrographis          Andrographolid  labdane        L. donovani
panicuiata(Kalmegh)   diterpenoid
Medicinal plants      8 plant species out of 94      L.
from Yanesha          EtOH extracts                  amazonensis

Plant compounds       IC (50) in             In vivo effect
                      amastigotes

Chalcones
Chinese liquorice     1 [micro]g/ml(IC (95)   2.5mg/kg b.w. i.l.
(roots)                                      and i.p. caused 50%
                                             reduction in lesion
                                             size in BALB/c
                                             mice
                      0.9 [+ or -] 0.4       20 mg/kg b.w., i.p.
                      [micro]M               and p.o. caused 98%
                                             reduction in
                                             hamsters and
                                             [Greater than] 85%
                                             reduction in BALB/c
                                             mice respectively
                      0.42-6.1 [micro]M      In hamsters 20
                                             mg/kg b.w. i.p.
                                             caused 97% whereas
                                             Pentostam (400
                                             mg/kg b.w.) caused
                                             94% reduction of
                                             parasitic burden in
                                             Iiver
Piper aduncum         24 [micro]g/ml         -
(Piperaceae)
                   1 [micro] g/ml(IC (57))   200 [micro] g/ml, j.
                                             p. caused 60%
                                             reduction
                                             200 [micro] g/ml,
                                             caused 90%
                                             reduction in
                                             lesional size in
                                             infected BALB/c
                                             mice
                      0.39-0.41 [micro]g/ml  -
                      0.03 [micro] g/ml
Psorothamnus polyden  5.0 [+ or -] 1.3 to    -
ius                   25.0 [+ or -] 4.4
                      [micro]g/ml
                   At 12.5 [micro]g/ml       -
                      (i)96 [+ or -] 2.
                      (ii)41 [+ or -] 10.
                      (iii) 30 [+ or -] 8%
                      reduction in parasite
                      load
Piper rusbyi          -                      5 mg/kg b.w., s.c.
                                             caused 32.17%
                                             reduction in
                                             lesional size in
                                             BALB/c mice
Flavonoids
Vitex negundo      12.5 [micro] M(IC (70))   3.5 mg/kg b.w,,
                                             s.c. caused 80%
                                             reduction in
                                             parasite load in
                                             hamsters
Fagopyrum esculentum  45.5 [micro]M          14 mg/kg b.w., s.c.
(buck wheat)               (IC (70))         caused 90%
                                             reduction in
                                             parasite load in
                                             hamsters
Kalanchoe pinnata     -                      8mg/day, p.o, as
(Crassulaceae)                               glucantime in
                                             BALB/c MICE
                      500 [micro]g/ml        320mg/kg b.w.,
                      (IC(58))               intragastric gavage
                                             reduced parasite
                                             burden by 70%
                      -                      8 mg/kg b.w.
                                             Pentostam caused
                                             62% inhibition
(2006b)
                      -                      Effective at 400
                                             mg/kg b.w., p.o.
                                             reduced parasite
                                             burden 4 fold than
                                             control infection,
                                             comparable with
                                             Pentostam (72 mg/kg
                                             b.w.) Treatment
(2006a.b)
                   - (ii) 45 [micro]g/ml     At 16 mg/kg, p.o.
                      (iii) 1 [micro]g/ml    (i)65% (ii)57%,
                                             (iii) 76% reduction
                                             in parasitic burden
                                             in BALB/c mice
                      20[micro]g/ml          Pentostam(20 mg/kg
                                             b.w.)caused 62%
                                             inhibition
Piper betle L.        5.45[micro]g/ml        -
                      9.31[+ or -]0.53
                      [micro]g/ml
Tanacetum          5 [micro]g/ml (IC (45))   -
parathenium (L)
Schultz Bip
Bidens pilosa L.      42.6[micro]g/ml and    -
(Asteraceae) and      69.6[micro]g/ml
Punica granatum L.
(Puniceae)
Saponins
Ivy Hedera helix      Comparable with        -
(Araliaceae)          meglumine antimonate
Hedera colchika       0.41 [+ or -]0.04      -
                      [micro]M 0.35 [+ or -]
                      0.06 [micro]M 0,068[+ or
                      -]0.002 [micro].M 0.46
                      [+ or -] 0.03 [micro]M
                      0.03 [+ or -] 0.003
                      [micro]M
Maesa balansae        7 ng/ml 14ng/ml        0.2 mg/kg b.w.,
(Myrsinaceae)                                s.c. 0.4 mg/kg
                                             b.w., s.c. caused
                                             [Greater than]90%
                                             inhibition
                      0.285 [micro]g/ml      Amphotericin B
                      5.6 [micro]g/ml        ([Greater
                                             than]10mg/kg.
                                             b.w.)
                                             Stibogluconate (40
                                             mg/kg, b.w.) caused
                                             90%  inhibition.
                                             Amphotericin B (5
                                             mg/kg. b.w.) caused
                                             100% reduction in
                                             BALB/c mice
Pera benensis         10[micro]g/ml          In BALB/c mice
                       (IC(83.5))
                      50 [micro]g/ml         Less potent than
                           (lC(85))          glucantime
                      10 [micro]g/ml (lC     50mg/kg/dayi.l.as
                      (65))                  potent as
                                             glucantime
                      10 [micro]g/ml         -
                          (IC (89))
Cephaelis             1.98 [+ or -] 0.04     -
                      [micro]M
camponutans
                      9.75 [+ or -]  1.13    -
                      [micro] M
Stephania dinklagei   36.1 [micro]M          -
                      9.75 [+ or -] 0.45     -
                      [micro]M
Helietta apiculata    -                      10 mg/kg b.w.,
                                             s.c.,
                                             caused [Greater
                                             than]95%
                      -                      95.2% decrease in
                                             parasite load in
                                             BALB/c mice
Alkaloids
Enantia chlorantha    -                      416 mg/kg in
(Annonaceae)                                 hamsters, i.m.
                                             caused 56%
                                             suppression
                                             208 mg/kg resulted
                                             in 84% suppression
Berberis aristata     2.5 [micro]g/ml (IC    50 mg/kg, b.w.,
                      (75))                  i.p.
(Berberidaceae)                              in hamsters caused
                                             90% reduction in
                                             parasitic burden,
                      2.5 [micro]g/ml (IC    similar to
                      (76))
                                             Pentamidine
                                             (50 mg/kg, b.w.)
                                             on
                                             8th day of post
                                             treatment
Ancistrocladus        4.1 [micro]g/ml        -
ealaensis
                      10.0 [micro]g/ml
                      49.0 [micro]g/ml
A. congolensis        18.8 [micro]g/ml       -
                      19.3 [micro]g/ml
                      47.0 [micro]g/ml
                      1.6 to [Greater
                      than]30 [micro]g/ml
A. likoko             5.9 [micro]g/ml        -
                      5.5 [micro]g/ml
A. tanzaniensis                              -
                      1.8 [micro]g/ml
                      1.6 [micro]g/ml
                      2.9 [micro]g/ml
                      0.305 [micro]g/ml
A. griffithii                                -
                      3.1 [micro]g/ml
                      18.3 [micro]g/ml
                      47.2 [micro]g/ml
Leaves of Tabemae-    38 [+ or -] 5.0        -
                      [micro]g/ml
montana
catharinensis
Galipea                                      BALB/c mice,
longi-                                       50mg/b.w., i.I.
flora                                        decreased parasite
(Rutacea)                                    load by
                      -                      (i) 96%.
                                             (ii)90%
                                             (iii)95%
                                             BALB/c mice
                                             0.54 mmol/kg, s.c.
                                             caused 86.6%
                                             reduction in
                                             parasitic load
Thamnosma             1 [micro]M caused      -
rhodesica             48.6 [+ or -] 2.7%
                      and
                      1 [micro]M caused
                      0.5 [+ or -] 0.03%
                      parasite
                      survival
Nuphar lutea          0.65 [micro]g/ml       -
(Nymphaeaceae)
                      40 [micro]g/ml         -
                      0.5 [micro]g/ml caused
                      71.6 [+ or -] 10.9%
                      inhibition
Croton pullei var.    19.8 [micro]M          -
glabrio
(Euphorbiaceae)
Indole alkaloids
Aurones               1.4 [micro]g/ml        -
Lignans
Haplophyllum          0.2 [+ or -] 0.05      -
                      [micro]M
bucharic[micro]M
(Rutaceae)
                      0.028 [+ or -] 0.008
                      [micro]M
Tannins
                      0.8-10.6 nM            -
                      10.6nM
                      0.30 nM
Terpenoids
Monoterpenes
Leaves of Croton      8.7 ng/ml              -
cajucura
(Euphorbiaceae)
Sesquiterpene
Artemisia annua       30 [micro]M            -
                      22 [micro]M            In BALB/c mice,
                                             25 mg/kg b.w.,
                                             p.o.
                                             caused 86%
                                             parasite removal,
                                             similar to SAG
                                             (20 mg/kg, b.w.)
                                             treatment
                      3 [micro]M             200 mg/kg b.w.,
                                             p.o.
                                             decreased lesions
Triterpenes
Betula sp.            4.1 [micro]M           10 mg/kg b.w.,
                                             i.m.
                                             caused 92%
                                             reduction in
                                             parasite burden in
                                             hamsters
Pourouma              27 [micro]g/ml         -
guianensis
(Moraceae)
                      11 [micro]g/ml
                      83 [+ or -] 2
                      [micro]g/ml
Glycyrrhizza glabra   4.6 [micro]g/ml        50 mg/kg b.w., i.p.
L (Licorice)                                 completely reduced
                                             parasitic burden in
                                             BALB/c mice
Polyaithia            5.79 [+ or -] 0.31     250 mg/kg b.w.,
longifolia            [micro]g/ml            p.o. caused 91 [+
(Annonaceae)                                 or -] 2% and
                      5 [micro]/ml           40mg/kg, b.w.
                                             caused 95.5 [+ or
                                             -] 1.22% reduction
                                             in parasite burden
Oxylipin Tridax       0.48 [micro]M          -
procumbent
(Asceraceae)
                      0.27 [micro]M          -
Momordica             -                      300 mg/kg i.m.
                                             10 mg/kg b.w., i.m.
                                             Both cone, caused
                                             100% reduction in
                                             parasitic burden in
                                             hamsters
Himatanthus sucuuba   15.7 [micro].g/ml      50 mg/kg b.w. p.o.
Latex (Apocynaceae)                          caused 74%
                      20 [micro]             -
                       g/ml(IC(80))
                      -                      I mg/kg, b.w.
                                             caused 43% parasite
                                             removal in BALB/C
                                             mice
Tinospora sinensis    29.8 [+ or -] 3.4      500 mg/kg b.w.,
                      [micro]g/ml            p.o. Caused 76.2 [+
                                             or -] 9.2% parasite
                                             removal
                      17.6 [+ or -] 4.1      250 mg/kg b.w.,
                      [micro]g/ml            p.o. caused 72.8 [+
                                             or -] 4.0%
                      3.3 [micro] g/ml       50 mg/kg, b.w.
                                             caused 93.3 [+ or
                                             -] 4.1% parasite
                                             removal in
                                             hamsters
Miscellaneous
Withania somnifera    63 [+ or -] 6.0        -
(Aswagandha)          [micro] g/ml
                      9.5 [+ or -] 3.0
                      [micro].g/ml
                      0.052 [+ or -] 0.2
                      [micro].g/ml
Allium sativum L.     67.0 [+ or -] 5.0      -
(Garlic)              [micro].g/ml
                      13.5 [+ or -] 2.0
                      [micro].g/ml
Allium sativum L.     50 [micro].M(IC (90))  -
(Garlic)
Podolepsis hie        8.29-8.59 [micro]g/ml  -
raciodes
(Asceraceae)
Zanthoxylum           _                      10mg/kg b.w. i.l.
chiloperone var.                             caused 77.6%
angustifolium
                      -                      28 mg/kg caused
                                             90.9% parasite
                                             removal in BALB/c
                                             mice
Plant compounds       IC (50) in             In vivo effect
                      amastigotes
Aloe vera             6.0 [micro]g/ml        15 mg/kg. b.w.,
                                             s.c. reduced
                                             [Greater than]90%
(2007a,b, 2008)
                      -                      20 mg/kg, b.w.
                                             reduced 57.1%
                                             parasitic burden in
                                             BALB/c mice
Chenopodium           -                      5 mg/ kg b.w. i.l.
ambrosioides L.                              or p.o. was
(Chenopodi- aceae)                           effective. similar
                                             to treatment with
                                             Sb (28 mg/kg. b.w.)
                                             in BALB/c mice
                      -                      51.4 mg/kg, p.o.
                                             caused  50%
                                             reduction in
                                             lesions, showed
                                             better efficacy
                                             than Glucantime (28
                                             mg/kg, b.w.) and
                                             Pentamidine
                                             (4mg/kg. b.w.)
                                             while Amphotericin
                                             B (1 mg/kg, b.w,)
                                             was ineffective. in
                                             BALB/c mice
Piper auritum         22.3 [+ or -] 1.8      -
                      [micro]g/ml
                      0.03 [+ or -] 0.002    -
                      [micro]g/ml
Physalis angulata     0.21 [micro]M          -
                      0.18 [micro]M
Peganum harmala       41.0 [+ or -] 1.53     100 mg/ kg. b.w.,
                      [micro]g/ml            p.o. caused 79.6 [+
                                             or -] 8.07%
                      5 [micro]g/ml          40 mg/kg, b.w.
                                             caused 95.5 [+ or
                                             -] 1.22%
parasite removal in
hamsters
N. arbortristis L     -                      20 mg/kg b.w., p.o.
(Night jasmine)                              caused 84% parasite
                                             removal in hamsters
                                             and no hepatotoxic-
                                             ity/neurotoxicity.
Sweria chirata        -                      2.5 mg/kg b.w.,
                                             s.c. resulted in
                                             34%  parasite
                                             removal in hamsters
Ampelocera edentula   -                      50 mg/kg b.w., i.l.
                                             was more effective
                                             than Glucantime
Desmodium gangeticum  -                      250 mg/kg b.w.,
                                             p.o. reduced 41.2
                                             [+ or -] 5.3% and
                                             66,7 [+ or -]
                                             6.l%parasite burden
                                             respectively in
                                             hamsters
Quassia amara         At 25 [micro]          -
                      /ml caused 70.45%
                      elimination of
                      parasites
Andrographis          -                      2.5 mg/kg b.w.,
panicuiata(Kalmegh)                          s.c. resulted in
                                             50% decrease in
                                             Parasite burden in
                                             hamsters
Medicinal plants      [Greater than] 10      -
from Yanesha          [micro]g/ml

Plant compounds       Toxicity                References
Chalcones
(roots)               monocytes by 30%.       1994)
                      toxic.                  Zhai et al.(1999)
                      -                       Zhai et al.(1999)
(Piperaceae)          macrophages             al. (1999a,b)
                      in BALB/c Mice
                      g/ml                    Kiderlen (2001)
                      macrophages
ius                   -] 12.3 [micro]g/ml     Werbovetz (2005)
                      [micro]g/ml
Piper rusbyi          -                       al.(2007)
Flavonoids
Vitex negundo         Tlymphoblasts           al.(2000)
(buck wheat)          Tlymphoblasts           (2000)
(Crassulaceae)        [micro]g/ml             (1995, 1999)
                                              (2009)
                                              Muzitano et al.
(2006b)
                      -                       Muzitano et al.
(2006a.b)
                                              (2010)
Piper betle L.        68[micro]g/ml           (2008)
                      100[micro]g/ml          (2009)
Schultz Bip           [micro]g/ml             (2010)
(Puniceae)            IC (50) in mouse        Garcia et al.
                      macrophages 153.1 [+    (2010)
                      or -]3.1[micro]g/ml 289.3
                      [+ or -]3.7[micro]g/ml
Saponins
Ivy Hedera helix      IC (50) in human        Majester-Savornin
(Araliaceae)          monodutes = 0.45        et al. (1991)
                      [micro]g/ml
Hedera colchika       IC (50) in THPI human   Ridoux et
                      monocytes 3.45[+ or     al.(2001)
                      -]0.25 [micro].M 4.57 [+
                      or -] 0.35 [micro]M 0.75
                      [+ or -]0.03 [micro].M
                      30[+ or -]8[micro].M 10[+
                      or -]2[micro]M
Maesa balansae        IC (50) in human        Maes et al.
(Myrsinaceae)         fibroblasts was 0.5     (2004). Germonprez
                      and 0.1 [micro]g/ml.     et al. (2005)
                      respectively
                      [Greater than]32
                      [micro]g/ml
                      [Greater than]32
                      [micro]g/ml
Pera benensis         Non toxic to            Fournet et al.
                      macrophages at 10       (1992a, 1992b)
                      [micro]g/ml
Cephaelis             IC(50) in KB            Camacho et al.
camponutans           cells = 11.80 [+ or -]
                      2.18 [micro] M(2004)
Stephania dinklagei   ND                      Camacho et al.
                                              (2000)
                      332.5 [+ or -] 2.5
                      [micro]g
Helietta apiculata
                                              (2010)
Alkaloids
Enantia chlorantha    Weight loss was         Vennerstrom et
                                              al.
(Annonaceae)          evident at              (1990)
                      416 mg/kg, b.w.,
                      i.m.
Berberis aristata     -                       Ghosh et
                                              al.(1985)
(Berberidaceae)
Ancistrocladus        IC(50) in L6,rat        Bringmann et al.
ealaensis             myoblasts, was          (2000)
                      [Greater than]90
                      [micro]g/ml
A. congolensis        IC(50) in L6 rat        Bringmann et al.
                      myoblasts was 33.4      (2002a, 2008)
                      to [Greater than]90
                      [micro]g/ml
                      IC(50) in L6 rat
                      myoblasts, from
                      68.0 to [Greater
                      than]90 [micro]g/ml
A. likoko             IC(50) in L6            Bringmann et al.
                      myoblasts was           (2003a)
                      36.6 [micro]g/ml
A. tanzaniensis       IC(50) in L6            Bringmann et al.
                      myoblasts,              (2003 b. 2004)
                      6.4 [micro]g/ml
                      8.1 [micro]g/ml
                      28.3 [miocro]g/ml
                      -
A. griffithii         IC(50) in L6 rat        Bringmann et al.
                      myoblasts               (2002b)
                      14.2 [micro]g/ml
                      35.8 [micro]g/ml
                      -
Leaves of Tabemae-    Non toxic up to         Scares et
                                              al.(2007)
montana               100 [micro]g/ml in
catharinensis         mouse
                      macrophages
Galipea               LD (50) in BALB/c       Fournet et al.
longi-                mice was                (1996)
flora                 [Greater than]400
                      mg/kg, b.w.
(Rutacea)
                                              Fournet et al.
                                              (1993)
                                              Fournet et al.
                                              (1994b)
                      -
Thamnosma             Non toxic up to         Ahua et al.
                                              (2004)
rhodesica             10 [micro]M
Nuphar lutea          IC(50)                  El-On et
                                              al.(2009)
(Nymphaeaceae)        in mouse peritoneal
                      macrophages = 2.1
                      [micro]g/ml
                      whereas, IC (50) in
                      paramomycin = 4000
                      [micro]g/ml
                                              Ozer et al.
                                              (2010)
Croton pullei var.    Non toxic up to         Guimaraes et al.
glabrio               79 [micro]M mouse       (2010)
(Euphorbiaceae)       peritoneal
                      macrophages
Indole alkaloids
Aurones               IC(50) ranged from      Kayser et al.
                                              (1999)
                      2.32 to 25 [micro]g/ml
                      in
                      murine bone
                      marrow derived
                      macrophages
Lignans
Haplophyllum          IC(50) in human         Di Giorgio et al.
bucharic[micro]M      monocytes was           (2005)
(Rutaceae)            35.2 [micro]M
Tannins
                      EC(50) in RAW 264.7.    Kolodziej et al.
                      mouse                   (2001a,b)
                      macrophages
                      ranged from 7.8 to
                      56 nM
Terpenoids
Monoterpenes
Leaves of Croton      Non toxic to            do Socorro et al.
cajucura              mammalian cells at      (2003)
(Euphorbiaceae)       cone, used (data
                      not included)
Sesquiterpene
Artemisia annua       Non toxic to            Yang and Liew
                      macrophages up to       (1993)
                      500 [micro]M
                                              Sen et al.
                                              (2007a,
                                              2010b)
Triterpenes
Betula sp.            IC(50) inTHP1,          Alakurtti et al.
                      human monocytes         (2010)
                      was 12.5-50 [micro]M     Chowdhury et al.
                                              (2003)
Pourouma              -                       Torres-Santos et
                                              al.
guianensis                                    (2004)
(Moraceae)
Glycyrrhizza glabra   At cone. [Greater       Ukil et al.(2005)
L (Licorice)          than]30 [micro] M was
                      toxic to mouse
                      peritoneal
                      macrophages
Polyaithia            Non toxic up to 200     Misra etal.(2010)
longifolia            [micro]g/ml in J774A.1
(Annonaceae)          mouse macrophages
Oxylipin Tridax       Non toxic up to 3       Martin-Quintal et
procumbent            [micro]M in bone marrow    al.(2010)
(Asceraceae)          derived macrophages
Momordica             IC(50) in hamster       Gupta et al.
                      macrophages was         (2010b)
                      [Greater than]200
                      mg/L
Himatanthus sucuuba   Non toxic to mouse      Soares et
Latex (Apocynaceae)   Peritoneal macrophages  al.(2010)
                      tip to 200 [micro]g/ml
                      (IC (75))
                      -
                      -
Tinospora sinensis    In J774.  mouse         Singh et al.
                      macrophages IC(50) =    (2008)
                      94.2 [+ or -]  11.6
                      [micro]g/ml And [Greater
                      than]100 [micro] g/ml
                      IC(50) = 35 p-g/ml in
                      macrophages
Miscellaneous
Withania somnifera    Non toxic toJ774,       Sharma et al.
(Aswagandha)          mouse macrophages up    (2009)
                      to 100[micro].g/ml
Allium sativum L.     Non toxic to mouse      Sharma et al.
(Garlic)              macrophages J774 up to  (2009)
                      100 [micro].g/ml
Allium sativum L.     Non toxic to BALB/c     Salem and
(Garlic)              mouse macrophages up    Werbovetz (2006)
                      to 100 [micro]M.
Podolepsis hie        IC (50) in macrophages  Kayser et al.
raciodes              ranged from 11.5 to     (2003b)
(Asceraceae)          [Greater than]25
                      [micro]g/ml
Zanthoxylum           LD50 in mouse was       Ferreira et al.
chiloperone var.                              (2002)
angustifolium
                      [Greater than]400
                      mg/kg b.w.
Plant compounds       Toxicity                References
Aloe vera             Non toxic to monocyte   Dutta et al.
                      s and macrophages up
                      to 300 [micro]g/ml
(2007a,b, 2008)
Chenopodium           Non toxic in BALB/c     Patricio et al.
ambrosioides L.       mice up to 5 mg/kg      (2008)
(Chenopodi- aceae)
                      Non toxic up to 150     Monzote et al.
                      mg/kg in Animals        (2009)
Piper auritum         IC (50) in mouse        Monzote et al.
                      peritonealmacrophages   (2010)
                      was 106.4 [+ or-] 3.4
                      [micro]g/ml
                      5.8 [+ or -]
                      0.5[micro]g/ml
Physalis angulata     Non toxic at conc.      Guimaraes et al.
                      used for amastigotes    (2009)
Peganum harmala       No IC (50) was found    Khaliq et al.
                      in J774A.l, mouse       (2009)
                      macrophage up to
                      [Greater than]200
                      [micro]g/ml
parasite removal in
hamsters
N. arbortristis L     Non toxic to U937 cell  Poddar et al.
(Night jasmine)       line up to 100          (2008)
                      [micro]g/ml
Sweria chirata        At 2.5 mg/kg b.w.,      Medda et al.
                      SGPTand alkaline        (1999)
                      phosphatase activity
                      was unchanged
Ampelocera edentula   -                       Fournet et al.
                                              (1999)
Desmodium gangeticum
Quassia amara         In macrophages IC (50)  Bhattacharjee et
                      = 100 [micro]g/ml          al. (2000)
Andrographis          Non toxic at 2.5        Sinha et
panicuiata(Kalmegh)   mg/kg, b.w. to          al.(2000)
                      hamsters
Medicinal plants      ND                      Valadeau el al.
from Yanesha                                  (2009)


Natural compounds that have shown promising antileishmanial activities are diverse in character and include phenolics, napthylisoquinoline alkaloids, sesquiterpene lactones including Luteolin (Mittra et al. 2000), Quassin (Bhattacharjee et al. 2009), Aloe vera (Dutta et al. 2007a,b, 2008). Artemisinin (Sen et al. 2007a, 2010b), and Berberine Chloride (Saha et al. 2009). In fact, as the WHO has estimated that approximately 80% of the world's inhabitants rely on traditional medicines for their health care (Newman and Cragg 2007), harmonization of traditional and modern medicine should be an abiding principle of pharmacologists (WHO 2000). Accordingly, this study summarizes the array of natural products (crude plant extracts, semi-purified fractions and chemically defined molecules) which have been evaluated for Leishmaniasis, with a view to provide novel drug targets (Table 1).

Mechanisms of action of plant derived compounds

Several promising antileishmanial compounds have been reported over the past few years based on their comparable efficacy with established antileishmanial drugs, using standard in vivo models. Once a promising candidate is identified, toxicology studies of those are then necessary to establish that the compound of interest possesses an adequate therapeutic index (Richard and Werbovetz 2010). Additionally, it is also valid to study the putative mechanism(s), as for example, kinetoplastid topoisomerase (I and II) are potential targets based on their structural differences with human type I DNA topoisomerases, making the enzyme an attractive target for chemotherapeutic intervention (Capranico et al. 2004). Topoisomerase inhibitors fall into two general categories namely (a) compounds that stimulate the formation of covalent enzyme-DNA complexes or topoisomerase poisons (class I inhibitors) and (b) products that interfere with enzymatic functions of the enzyme or class II inhibitors (Capranico et al. 2004; Balana-Fouce et al. 2006).

Another potential target is the parasite mitochondrion because of its unique structure and function compared to its mammalian host; maintenance of the mitochondrial trans-membrane potential is essential for the survival of cells and study of mitochondrial trans-membrane potential has become a focus of apoptosis regulation (Sen and Majumder 2008).

Another aspect is exploiting metabolic differences which completely distinguishes from the host and thereby generates the putative role of biochemical targets like glycolytic enzymes, sterols, purine, pyrimidine, cysteine proteases, protein kinases, fumarate reductases and polyamine biosynthesis pathways of parasites (Balana-Fouce et al. 1998; Le Pape 2008).

Leishmania possess a unique relatively weak trypanothione dependent anti-oxidant system in which the ubiquitous glutathione/glutathione reductase system is replaced by parasite specific trypanothione (T[[SH.sub.2]]) and tiypanothione reductase (TryR). The dithiol trypanothione is composed of gluthathione and spermidine and is the key molecule for the synthesis of DNA precursors, detoxification of hydroperoxides, and sequestration/export of thiol conjugates (Fairlamb and Cerami 1992). Different rate limiting enzymes that play a major role in tiypanothione biosynthesis include [gamma]-gIutamylcysteine synthase([gamma]-GCS), Ornithine decarboxylase (ODC) necessary for the synthesis of gluthathione and spermidine respectively along with Tiypanothione synthase. Therefore, these rate limiting enzymes can act as good chemotherapeutic targets. Trypanothione reductase is a key enzyme in the redox metabolism of Leis/imania responsible for the transfer of reducing equivalents from the NADP+/NADPH couple from T[[SH].sub.2] enzymes of the tryparedoxin peroxidase (TryP) family. Therefore enzymes of the trypanothione dependent antioxidant system are potential antitrypanosomal drug targets (Schmidt and Krauth-Siegel 2002). Moreover, absence of catalase and classical glutathione peroxidases in Leishmania renders the parasite more susceptible to free radical mediated apoptosis (Sen et al. 2010a).

As Leishmaniasis is associated with immunological dysfunction of T cells, natural killer cells and in particular, incapacitation of macrophages which ultimately leads in establishment of the parasite, experimental approaches have included developing antileishmanial compounds capable of recovering the Th1 immune response (Murray 2001), via activation of macrophages, through enhanced release of NO (Kaye et al. 2004).

Phytoconstituents isolated from plants that have shown potent antileishmanial activity include phenolics like Aurones, Lignans, Chalcones, Flavonoids, Isoflavonoids, Saponins, Quinones, Alkaloids, Tannins, Terpenoids. Iridoids, Terpenes, Oxylipins and miscellaneous sources of plant secondaiy metabolites (Table 1).

Chalcones

Licochalcone A, an oxygenated chalcone isolated from the roots of Chinese plant liquorice alters the ultrastructure of parasite mitochondria (Zhai et al. 1995) and causes inhibition of mitochondrial dehydrogenases (Zhai et al. 1999), more specifically, inhibition of fumarate reductase in the parasite respiratory chain (Chen et al. 1993, 2001). Furthermore, as the [IC.sub.50] in amastigotes was lower than promastigotes, activation of macrophages has been proposed as an additional mechanism (Zhai et al. 1999). Kayser and Kiderlen (2001) studied 20 naturally occurring chalcones wherein their anti-parasitic activity appeared to increase in the presence of oxy-substituents and methoxy group while introduction of hydrophilic substitutes reduced their leishmanicidal activity.

Flavonoids

Flavonoids are widely distributed in the plant kingdom and a search for their anti-parasitic activity have yielded compounds like Luteolin isolated from Vitex negundo and Quercetin derived from Fagopyrum esculentum (Mittra et al. 2000). Luteolin has been shown to inhibit the synthesis of parasite DNA via inhibition of topoisomerase II mediated linearization of kDNA minicircles, culminating in arresting of cell cycle progression (Mittra et al. 2000); the scenario was similar with regard to Quercetin (Mittra et al. 2000). Additionally, quercitin (aglycone) can chelate iron, which translates into a decreased availability of the iron dependent ribonucleotide reductase, a rate limiting enzyme for DNA synthesis (Sen et al. 2008). In addition, its combination with SSG enhanced parasite removal as compared to quercetin treatment alone (93% vs. 82%, Sen et al. 2005). A leafy extract of Kalanchoe pinnata (Crassulaceae, Kp), rich in flavonoids exhibited antileishmanial activity, by increasing generation of reactive nitrogen intermediates that was further enhanced by the addition of IFN[gamma] (da Silva et al. 1995; Gomes et al. 2010). Kp also exhibited reduced delayed type hypersensitivity (DTH) responses in Leishmania infected mice and further studies revealed that Quercetrin, a flavonoid isolated from Kp was one of the contributory phytoconstituents (Muzitano et al. 2006a,b, 2009). An EtOH extract of Piper betle L triggered mitochondria mediated apoptosis in Leishmania parasites (Sarkar et al. 2008) as also a eugenol rich PB-BM (methanolic extract) showed antileishmanial efficacy that occurred via enhanced production of reactive oxygen species which triggered apoptosis (Misra et al. 2009) . Parasites treated with an [IC.sub.50] concentration of guaianolide from Tanacetum parthenium (L.) Schultz Bip showed morphological changes (Da Silva et al. 2010).

Saponins

Studies with [alpha]-hederin and [beta]-hederin isolated from Hedera helix as also Hederacolchiside A1 isolated from Hedera colchica exhibited strong anti-proliferative activity, attributed to their ability to react with Leishmania membranes, induce a decrease in membrane potential and ultimately cause loss of membrane integrity (Ridoux et al. 2001).

Quinones

Plant secondary compounds like Plumbagin isolated from Pera benensis exhibited its effectivity via increased generation of free radicals in parasites; however, its ability to induce mammalian topoisomerase II mediated DNA cleavage suggests its potential cytotoxicity towards host cells (Fournet et al. 1992a, 1992b; Fujii et al. 1992), Diospyrin is another napthoquinone isolated from D. montana Roxb. (Ebenaceae) that also exhibited antileishmanial activity via free radical generation, inhibition of DNA topoisomerase I leading to an apoptosis like cell death in promastigotes; however its efficacy in amastigotes has not been studied (Hazra et al. 2002; Mukherjee et al. 2009).

Alkaloids

Alkaloids have been abundantly used against Leishmaniasis and include Berberine Chloride isolated from Berberis aristata, that inhibits amastigote respiration by targeting mitochondrial enzymes, as also interferes with the macromolecular biosynthesis of amastigotes (Ghosh et al. 1985). More recent studies have revealed that Berberine Chloride triggers a free radical mediated, caspase-independent apoptosis-like death in promastigotes (Saha et al. 2009). In infected neutrophils, Berberine Chloride induces apoptosis via generation of an oxidative burst which translated into a reduction in parasite load whereas in infected macrophages, it modulated mitogen activated protein kinases (MAPKs), regulatory enzymes for apoptosis and inflammation. It caused increased phosphorylation of p38 MAPK and concomitant reduction in extracellular signal related kinase. ERK1/2, thus highlighting MAPKs as a potential chemotherapeutic target in Leishmaniasis (Saha et al. 2010). A superficial fluid of an EtOH fraction (AF3) containing alkaloids coronaridine (7%) and voacangine (53%) isolated from leaves of Tabernaemontana catharinensis has been shown to have leishmanicidal activity, independent of NO production in macrophages (Soares et al. 2007). However a partially purified alkaloid fraction (NUP) extracted from Nuphar Lutea, exhibited leishmanicidal activity that was both directly cytotoxic to parasites and via activation of NF-[kappa]B of infected macrophages leading to elevated production of NO (Ozer et al. 2010). Activity of the julocrotine, a glutarimide alkaloid from Croton pullei var. glabrior, was studied in L. amazonensis wherein it caused morphological changes in promastigotes, such as swelling of the mitochondrion, chromatin condensation, presence of membranous structures near the golgi complex, and appearance of vesicular bodies in the flagellar pocket (Guimaraes et al. 2010).

Lignans

Diphyllin isolated from Haplophyllum bucharicum (Rutaceae) displayed anti-proliferative activity in promastigotes by interacting with macromolecules, resulting in cell cycle arrest in the S-phase. However, in amastigotes, its activity was related to its ability to prevent parasite attachment to macrophages and their subsequent entry (Di Giorgio et al. 2005).

Tannins

In an extensive study by Kolodziej et al. (2001a,b); a series of proanthocyanidins and structural analogs were shown to exert an immunomodulatory activity, as they increased release of NO along with enhancement of expression of pro-inflammatoiy cytokines in host cells namely tumor necrosis factor-alpha (TNF-a) and interferon gamma (IFN-[gamma]). Similarly, polyphenol containing extracts and phenols, flavan-3-olgallocatechin tannins also upregulated mRNA expression of TNF-[alpha]. IFN-[gamma], inducible nitric oxide synthase (iNOS), lL-1. IL-12 and IL-18 in Leishmania infected macrophages (Kolodziej and Kiderlen 2005).

Terpenoids

Monoterpenes like Linalool isolated from leaves of Croton cajucara [Euphorbiaceae), effectively increased the production of NO in Leishmania infected macrophages, along with directly targeting the parasite as evidenced by mitochondrial swelling and alterations in the organization of nuclear and kinetoplast chromatin (do Socorro et al. 2003). With regard to studies with sesquiterpene lactones like Artemisinin and its derivatives, it has been proposed that the presence of an endoperoxide bridge within the compound selectively enhances generation of free radicals in the parasite (Krishna et al. 2004); iron has been shown to play a critical role in inducing the observed apoptosis in parasites (Meshnick et al. 1993; Yang and Liew 1993; Sen et al. 2010a). Additionally. Artemisinin increased production of NO and mRNA expression of iNOS to levels present in uninfected macrophages and enhanced the release of Th1 cytokines (IFN-[gamma]) suggesting that Artemisinin is directly parasiticidal and indirectly exerts an immunomodulatory activity (Sen et al. 2010b).

Dihydrobetulinic acid, an abundantly occurring triterpene showed antileishmanial activity via targeting of DNA topoiso-merases (both I, II) and preventing DNA cleavage, ultimately inducing apoptosis in L donovani (Chowdhury et al. 2003; Alakurtti et al., 2010). Terpenes like ursolic acid and oleanolic acid isolated from Pourouma guinensis also inhibited parasitic growth, but did not induce production of NO in macrophages and instead influenced the phagocytic activity of macrophages (Torres-Santos et al. 2004). A water soluble 18[beta]-glycyrrhetinic acid (GRA) isolated from Glycyrrhizza glabra L (Licorice) exhibited antileishmanial activity via triggering a curative Th1 cytokine response, concomitant with enhanced production of NO (Ukil et al. 2005). 16[alpha]-Hydroxycleroda-3, 13(14)Z-dien-15, 16-olide, a clerodane diterpene isolated from an ethanolic extract of Polyalthia longifolia inhibited parasite DNA topoisomerase I by directly interacting with the enzyme, terminating in an apoptotic mode of cell death (Misra et al. 2010).

Oxylipin

An oxylipin 3(S)-16, 17-didehydrofalcarinol isolated from Tridax procambens (Asteraceae) showed direct parasiticidal effect, independent of NO production in macrophages (Martin-Quintal et al. 2010). An aqueous extract (Momordicatin) isolated from Momordica charantia inhibited iron containing parasite superoxide dismutase (SOD), without affecting host SOD (Gupta et al. 2010b). As SOD is a key enzyme for attenuating oxidative stress, its inhibition would lead to increased generation of free radicals, that would be deleterious for the parasite, especially as it is known to have an inefficient antioxidant system (Jaeger and Flohe 2006). An EtOH extract and butanol fraction isolated from Tinospora sinensis induced an oxidative burst in macrophages by increasing production of ROS and NO resulting in parasite killing (Singh et al. 2008). Himatanthus sucuuba Latex (Apocynaceae) or HsL enhanced generation of NO and TNF-[alpha] along with inhibition of TGF-[beta] within macrophages (Soares et al. 2010).

Miscellaneous

G3, isolated from Withania somnifera (Withaferin A, steroidal lactone) exerted its parasiticidal activity via inhibition of protein kinase C (PKC), a central event for the induction of apoptosis following stabilization of the topoisomerase I-DNA complex (Sharma et al. 2009; Sen et al 2007b). A plant extract isolated from Allium sativum L. (Garlic) was proposed to act via multiple targets as it effectively disturbed thiol homeostasis, disrupted the plasma membrane integrity and increased release of Th1 pro-inflammatory cytokines (Sharma et al. 2009). The addition of SSG improved the activity of garlic possibly due to their synergistic immunomodulatory properties enhancing the protective Th1 response (Ghazanfari et al. 2000). Ajoene, an isolated fraction of the same caused morphological changes within the nuclear envelope, causing formation of large autophagic vacuoles and megasomes resulting in parasite death (Ledezma et al. 2002; Salem and Werbovetz 2006). Studies with a leafy exudate of Aloe vera, demonstrated its ability to effectively activate macrophages as evidenced by increased production of reactive oxygen species in infected macrophages along with directly causing cell cycle arrest in parasites (Dutta et al. 2007a,b). A hydroalcoholic extract (HCE) isolated from Chenopodium ambrosiodes L. (Chenopodiaceae) stimulated macrophages and increased production of NO, in draining lymph nodes (Patricio et al. 2008). Ascaridol (22%), an endoperoxide present within the essential oil of Chenopodium ambrosiodes helped in the formation of oxygen centered radical intermediates which mediated its anti-parasitic effect (Monzote et al. 2009). The antileishmanial activity of Physalins B and F extracted from plant species Physalis angulata suggested it was directly parasiticidal, independent of NO production (Guimaraes et al. 2009). Peganine hydrochloride dihydrate isolated from Peganum harmala induced an apoptotic like death by inhibition of DNA topoisomerase I activity, resulting in parasite cell death (Khaliq et al. 2009). Interestingly, Calceolarioside A, isolated from N. arbortrisds L>. (Night jasmine) showed better efficacy when combined with SSG (Poddar et al. 2008). Amarogentin isolated from Swertia chirata, a secoiridoid glycoside exhibited its inhibitory effect by binding to topoisomerase I thus preventing formation of the binary complex between topoisomerase I and DNA, causing parasite cell death (Medda et al. 1999). An EtOH extract of Desmodium gangeticum acted as an immunostimulant in infected macrophages, resulting in parasite removal (Singh et al. 2005). Quassin isolated from Quassia amara enhanced the host protective immune response by enhancing generation of NO and expression of iNOS both at a protein and at mRNA levels and by upregulating proinflammatory cytokines, TNF-[alpha] and IL-12 (Bhattacharjee et al. 2009). Picroliv, isolated from Picrorhiza kurroa, a hepatoprotector under phase III trials per se showed no leishmanicidal activity but potentiated activity of conventional drugs, SAG and Miltefosine in experimental model of Leishmaniasis (Mittal et al 1998; Gupta et al. 2005).

Future perspectives

Considering the limited repertoire of existing antileishmanial compounds, it is essential to preserve their efficacy along with continual development of new leishmanicidal compounds. Therefore along with understanding the molecular and biochemical characteristics of test compounds, it is equally important to mitigate chances of drug resistance, and in this regard, using herbal compounds in combination with conventional drugs are an attractive chemotherapeutic option worthy of future consideration (Wagner and Ulrich-Merzenich 2009).

Conclusions

The primary criteria of searching for new drugs effective in Leishmaniasis are its efficacy along with relatively lower side effects as compared to current therapeutic modalities. New therapeutic alternatives are even more desirable in the present scenario where pentavalent antimonial over the years gradually have acquired resistance (Sundar and Chatterjee 2006). Due to relative anergy of the pharmaceutical industry, the therapeutic armamentarium of available antileishmanial drugs remains limited, often leading people in endemic areas suffering from Leishmaniasis to depend upon traditional medicines to alleviate the symptoms. As the scientific evaluation of medicinal plants used in the preparation of folk remedies have provided modern medicine with effective pharmaceuticals, many investigators have tapped the plant kingdom. Success stories include the treatment of malaria and amoebiasis using the alkaloids, quinine and emetine obtained from Cinchona and Cephalis, respectively; in more recent times, Artemisinin, a sesquiterpene lactone derived from the herb Artemisia annua has been an invaluable addition (Golenser et al. 2006; Phillipson and Wright 1991). Generally, detection of plant secondary metabolites with leishmanicidal activity has been performed in promastigotes being easier to maintain under in vitro conditions. However, its efficacy must be complemented with evaluation in intracellular amastigotes as often compounds effective against promastigotes are equally toxic to host cells, thereby excluding their inclusion in further studies. It is also relevant to delineate the underlying mechanism(s) of action as it would open up new avenues for drug targeting that could be subsequently screened by high throughput assays.

The current study has highlighted a range of plant extracts exhibiting parasiticidal activity some of which also have a good safety index. Compounds with a safety index 9-20 fold included Chalcones (including Licochalcone, encapsulated formulations), Flavanoids (alcoholic extracts of P. betle). Saponins like Hederins and Hederacolchiside A1 isolated from Hedera colchica. Alkaloids (including Rhodesiacridone isolated from T. rhodesica; Ancistroealaine isolated from A. ealaensis; Ancistrocladidine isolated from A. Tanzaniensis, Terpenoids - sesquiterpenes like Artemisinin isolated from Artemisia sp., Oxylipin like HsL isolated from H. sucuuba and miscellaneous plant sources like Withaferin A isolated from W. somnifera, G3 isolated from A. sativum ([tilde]7.5 fold); leafy exudates isolated from A. vera. The safety index was even higher with Maesabalides III ([tilde]71 fold), Lignans like Diphyllin isolated from H. bucharicum ([tilde] 177 fold) and 200 fold with a Guainolide extracted from T. parthenium (Table 1). It could therefore be anticipated that compounds described in this review when complimented with studies in animal models of Leishmaniasis would yield new drug candidates that may enter the antileishmanial drug development pipeline.

Acknowledgements

RS is the recipient of a Senior Research Fellowship from Indian Council of Medical Research, Govt. of India. This work received financial assistance from Indian Council of Medical Research (ICMR), Council for Scientific and Industrial Research (CSIR) and Dept. of Science and Technology (DST), Govt. of India.

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(*) Corresponding author. Tel.: +91 33 2223 4135; fax: +91 33 2223 4135. E-mail address: ilatim@vsnl.net (M. Chatterjee).

Rupashree Sen, Mitali Chatterjee (*)

Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244 B, Acharya JC Bose Road, Kolkata, West Bengal 700020, India.
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Author:Sen, Rupashree; Chatterjee, Mitali
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
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Date:Sep 15, 2011
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