Review article
Leishmania treatment and prevention: Natural and synthesized drugs

https://doi.org/10.1016/j.ejmech.2018.10.022Get rights and content

Highlights

  • Various herbal agents show promising antileishmanial activity.

  • Promising synthesized agents with various core substructures were reported.

  • New drugs are needed due to the toxicity and resistance to current treatments.

  • A need to develop an effective vaccine with broad protection against leishmaniasis.

Abstract

Leishmaniasis affects over 150 million people all over the world, especially in subtropical regions. Currently used antileishmanial synthesized drugs are associated with some drawbacks such as resistance and cytotoxicity, which hamper the chances of treatment. Furthermore, effective leishmanial vaccines are not well developed. Promising chemotherapy, either from natural or synthetic compounds, was or still is the most promising treatment. This review focuses on recent findings in drugs used for the treatment of leishmaniasis including; chemical and natural antileishmanial moieties, different potential targets, as well as various trials of vaccination development. Special emphasis has been paid to the mechanisms of the drugs, their safety and where possible, the structure-activity relationship to enable guided future drug discovery.

Introduction

Leishmaniasis is a parasitic infection caused by the protozoan Leishmania parasites, which are transmitted by the bite of infected female phlebotomine sand flies. Leishmania has two life cycles: intracellular amastigotes in the mammalian host, and the promastigotes in the fly [1,2].

Leishmaniasis is endemic in more than 90 countries worldwide and at least 13 million people are estimated to be infected [3,4]. The diagnosis of leishmaniasis is limited by variations and subclinical manifestations of the disease. Leishmania mainly affects poor people in Africa, Asia, and Latin America; and is associated with malnutrition, population displacement, poor housing, and a weak immune system. Leishmaniasis currently threatens 350 million men, women, and children in 88 countries around the world [5,6]. An estimated 0.9 to 1.3 million new cases and 20,000 to 30,000 deaths are predicted to occur annually due to leishmaniasis [5,6].

There are four main forms of leishmaniasis: visceral (also known as kala-azar, and is considered as the most serious form of the disease), cutaneous (the most common), mucocutaneous, and post kala-azar [[7], [8], [9], [10]]. Cutaneous leishmaniasis (CL) is a neglected clinical form of public health importance. It is caused by several species of Leishmania, mainly L. tropica, L. major, L. amazonesis and L. Mexicana. The CL may be a Zoonotic cutaneous leishmaniasis (ZCL) or an anthroponotic cutaneous leishmaniasis (ACL) [[11], [12], [13]]. The other type of leishmaniasis is Mucocutaneous leishmaniasis, also known as “Espundia”, which is caused mainly by the species L. vianniabraziliensis. L. vianniapanamensis and L. amazonesis have also been reported to affect mucosal tissues [12]. Visceral leishmaniasis (VL, Kala-azar) is a growing public health challenge that is manifested by L. donovani and L. infantum infections.

Leishmania donovani infections are restricted to the (sub-) tropics of Asia and Africa, where transmission is mostly anthroponotic, while L. infantum occurs in the drier parts of Latin America as well as in the Mediterranean region, with domestic dogs serving as the main reservoir host [[14], [15], [16], [17]]. Finally, post Kala-azar dermal leishmaniasis is caused by the protozoan parasite L. donovani and is the most clinically and scientifically intriguing form of the disease since it generally develops as a sequela after a patient's apparent successful cure from visceral leishmaniasis [18,19].

There are several known antileishmanial drugs currently available, such as amphotericin B, antimonials, sitamaquine, pentamidine, paromomycin, and miltefosine. Generally, antileishmanial drugs have immunomodulatory activity and can stimulate the innate immune system [20], but several drawbacks manifest during the treatment regimen have been recorded. Pentavalent antimonials have been used to be the predominant drug for treatment of VL. However, these drugs were found to be toxic and have adverse side effects that can lead to fatality [21]. Pentamidine has also been previously used in the treatment of VL. Despite its effectiveness in the treatment of pentavalent antimony-resistant VL, its use has decreased due to the route of administration (injection) and the toxic side effects associated with the drug [22].

Miltefosine was the first oral drug used for the treatment of visceral and cutaneous leishmaniasis but due to its teratogenicity, prolonged treatment regimen, and high resistance potential, its use has declined [23,24]. Amphotericin B (AmB) has high leishmanicidal activity and its use results in fewer treatment failures and relapses. However, it causes nephrotoxicity and requires parenteral administration, which has led to its rejection as a first-choice treatment [25,26]. The usefulness of sitamaquine also is limited due to its severe nephrotoxicity, which can result in kidney failure as well as its potential to cause methemoglobinemia [27]. Paromomycin is an old aminoglycoside antibiotic that has been recently approved for use in the treatment of leishmaniasis. Drug resistance development, as well as common side effects such as ototoxicity and liver dysfunction, have been common drawbacks with this drug [28,29].

Although the range of antileishmanial drugs has expanded, the currently available drugs do not meet the increasing requirements of managing infection in different patient populations since drug resistance and toxicity have been reported for all the currently available drugs [21,[30], [31], [32], [33], [34]]. However, a combination of treatments for visceral leishmaniasis has been shown to be more effective and safer to use as they were found to decrease the duration of therapy and reduce the emergence of drug-resistant parasites [[35], [36], [37], [38], [39], [40], [41]].

The objective of this review is to provide an update on natural drugs, their semisynthetic derivatives and synthesized agents that show leishmanicidal activity. Given the problem of resistance, we also emphasize the structure-functional aspects of some new potential targets that may provide a new approach in the field of antileishmanial therapy, as well as research on the development of an effective vaccine.

Section snippets

Herbal antileishmanial agents

According to the World Health Organisation (WHO), the plant kingdom is the only option for developing a therapeutic agent that has both a high safety profile and cost-effectiveness for several health problems (WHO, 2015). For example, Allium cepa and Azadirachta indica are used for the treatment of skin disorders [42], citrulluscolocynthis, buckwheat, and chamomile are useful in treating cardiovascular diseases [43], and Salvia, Valeriana, and Hypericum are used as antiprotozoal agents [44].

Synthesized antileishmanial agents

Various heterocyclic moieties, in either single or fused systems, possess antileishmanial properties (Table 2). This section of the review discusses some of these heterocyclic moieties. Fig. 3 and Fig. 4 provide examples of synthesized antileishmanial agents.

Antileishmanial potential targets

The main problems associated with the currently available antileishmanial drugs are their side effects and the tendency of the parasite to develop resistance on long-term. These problems are also the main drivers for the development of new drug discoveries [117]. A target-based drug discovery approach is a new strategy to improve antileishmanial treatment. This approach depends on the identification of new potential targets and validation through biochemical analysis [[118], [119], [120], [121]

Vaccination

The development of a Leishmania vaccine has proven to be a challenging task. An effective immune protection has not yet been established. This is may be due to a limited knowledge about parasite pathogenesis. The immune responses of leishmnasis are complex and unclear. Patients affected with Leishmania are susceptible to reinfection due to problems with the currently used drugs and the lack of a prophylactic medicine. Therefore, there is a crucial need to develop an effective vaccine exhibiting

Conclusions and future perspective

The need for new antileishmanial drugs continues to be an urgent target for researchers due to the toxicity, adverse effects and developed resistance to current treatments. Among the vaccines developed for Leishmania, leishmanization and HbR-DNA appear to be the most promising, but intensive evaluation of leishmanization against various types of Leishmania should be carried out and good safety records of these techniques should be established before widespread use is considered. Given that most

Financial & competing interests disclosure

The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

References (198)

  • P. Boeck et al.

    Synthesis of chalcone analogues with increased antileishmanial activity

    Bioorg. Med. Chem.

    (2006)
  • V.S. Amato et al.

    Mucosal leishmaniasis . Current scenario and prospects for treatment

    Acta Trop.

    (2008)
  • L.E. Barata et al.

    Anti-leishmanial activity of neolignans from Virola species and synthetic analogues

    Phytochemistry

    (2000)
  • C. Chollet et al.

    In vitro antileishmanial activity of fluoro-artemisinin derivatives against Leishmania donovani

    Biomed. Pharmacother.

    (2008)
  • S.R. Peraza-Sanchez et al.

    Leishmanicidal evaluation of extracts from native plants of the Yucatan peninsula

    Fitoterapia

    (2007)
  • M.C. Vendrametto et al.

    Evaluation of antileishmanial activity of eupomatenoid-5, a compound isolated from leaves of Piper regnellii var. pallescens

    Parasitol. Int.

    (2010)
  • M. Morales-Yuste et al.

    Activity of (-) α-bisabolol against Leishmania infantum promastigotes

    Phytomedicine

    (2010)
  • M. de Medeiros et al.

    In vitro antileishmanial activity and cytotoxicity of essential oil from Lippia sidoides Cham

    Parasitol. Int.

    (2011)
  • M.E. Ferreira et al.

    Antileishmanial activity of furoquinolines and coumarins from Helietta apiculata

    Phytomedicine

    (2010)
  • X. Zhu et al.

    Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents

    Bioorg. Med. Chem. Lett

    (2016)
  • R. Adam et al.

    Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction

    Bioorg. Med. Chem.

    (2014)
  • S. Marhadour et al.

    Synthesis and biological evaluation of 2,3-diarylimidazo[1,2-a]pyridines as antileishmanial agents

    Eur. J. Med. Chem.

    (2012)
  • J.V. Faria et al.

    Synthesis and activity of novel tetrazole compounds and their pyrazole-4-carbonitrile precursors against Leishmania spp

    Bioorg. Med. Chem. Lett

    (2013)
  • C.A. Coy Barrera et al.

    seco-limonoids and quinoline alkaloids from Raputia heptaphylla and their antileishmanial activity

    Chem. Pharm. Bull. (Tokyo)

    (2011)
  • E. Sobarzo-Sanchez et al.

    Synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities

    PloS One

    (2013)
  • E. Palumbo

    Visceral leishmaniasis in children: a review

    Minerva Pediatr.

    (2010)
  • M. Islamuddin et al.

    Th1-biased immunomodulation and therapeutic potential of Artemisia annua in murine visceral leishmaniasis

    PLoS Neglected Trop. Dis.

    (2015)
  • M. Islamuddin et al.

    Leishmanicidal activities of Artemisia annua leaf essential oil against Visceral Leishmaniasis

    Front. Microbiol.

    (2014)
  • D. Stark et al.

    Post-kala-azar dermal leishmaniasis due to leishmania infantum in a human immunodeficiency virus type 1-infected patient

    J. Clin. Microbiol.

    (2006)
  • S. Shah et al.

    Post-kala-azar dermal leishmaniasis in HIV-positive patients: a study of two cases

    Indian J. Sex. Transm. Dis.

    (2010)
  • A. Badirzadeh et al.

    Cutaneous and post kala-azar dermal leishmaniasis caused by Leishmania infantum in endemic areas of visceral leishmaniasis, northwestern Iran 2002–2011: a case series

    Pathog. Glob. Health

    (2013)
  • L. McCall et al.

    Determinants for the development of visceral leishmaniasis disease

    PLoS Pathog.

    (2013)
  • A.M. Samy et al.

    Ecology of cutaneous leishmaniasis in Sinai: linking parasites, vectors and hosts

    Mem. Inst. Oswaldo Cruz

    (2014)
  • L.P. Carvalho et al.

    Effect of LACK and KMP11 on IFN-gamma production by peripheral blood mononuclear cells from cutaneous and mucosal leishmaniasis patients

    Scand. J. Immunol.

    (2005)
  • P. Navarro et al.

    In vitro leishmanicidal activity of pyrazole-containing polyamine macrocycles which inhibit the Fe-SOD enzyme of Leishmania infantum and Leishmania braziliensis species

    Parasitology

    (2014)
  • S.M. Duque-Benitez et al.

    Synthesis of novel quaternary ammonium salts and their in vitro antileishmanial activity and U-937 cell cytotoxicity

    Molecules

    (2016)
  • G. Bringmann et al.

    A novel leishmania major amastigote assay in 96-well format for rapid drug screening and its use for discovery and evaluation of a new class of leishmanicidal quinolinium salts

    Antimicrob. Agents Chemother.

    (2013)
  • H. Denise et al.

    Studies on the CPA cysteine peptidase in the Leishmania infantum genome strain JPCM5

    BMC Mol. Biol.

    (2006)
  • F. Kheirandish et al.

    Inhibition of leishmania major PTR1 gene expression by antisense in Escherichia coli, Iran

    J. Public Health

    (2012)
  • M. Castes et al.

    Characterization of the cellular immune response in American cutaneous leishmaniasis

    Clin. Immunol. Immunopathol.

    (1983)
  • B.S. McGwire et al.

    Migration through the extracellular matrix by the parasitic protozoan Leishmania is enhanced by surface metalloprotease gp63

    Infect. Immun.

    (2003)
  • B.L. Campos et al.

    Analysis of iron superoxide dismutase-encoding DNA vaccine on the evolution of the Leishmania amazonensis experimental infection

    Parasite Immunol.

    (2015)
  • O. Riede et al.

    Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine

    Gene Ther.

    (2015)
  • P.M. De Luca et al.

    Cutaneous leishmaniasis vaccination: a matter of quality

    Front. Immunol.

    (2016)
  • G.F. Späth et al.

    The role(s) of lipophosphoglycan (LPG) in the establishment of Leishmania major infections in mammalian hosts

    Proc. Natl. Acad. Sci. U.S.A.

    (2003)
  • R. Reithinger et al.

    Cutaneous leishmaniasis

    Lancet Infect. Dis.

    (2007)
  • L.F. Gonçalves de Oliveira et al.

    Natural products and phytotherapy: an innovative perspective in leishmaniasis treatment

    Phytochemistry Rev.

    (2016)
  • L. Proudfoot et al.

    Glycoinositolphospholipids of Leishmania major inhibit nitric oxide synthesis and reduce leishmanicidal activity in murine macrophages

    Eur. J. Immunol.

    (1995)
  • J. Sangshetti et al.

    Antileishmanial drug discovery: comprehensive review of the last 10 years

    RSC Adv.

    (2015)
  • C.M. Lezama-Davila et al.

    A new antileishmanial preparation of combined solamargine and solasonine heals cutaneous leishmaniasis through different immunochemical pathways

    Antimicrob. Agents Chemother.

    (2016)
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