Review articleNatural and synthetic coumarins as antileishmanial agents: A review
Graphical abstract
Introduction
Leishmaniasis is a neglected tropical disease (NTD) with serious socioeconomic and health impacts in society [1]. Endemic in more than 98 countries and associated with poor living conditions, this vector-borne disease presents mainly four clinical manifestations: cutaneous leishmaniasis (CL), diffuse cutaneous leishmaniasis (DCL), mucocutaneous leishmaniasis (MCL) and visceral leishmaniasis (VL). The nature of clinical manifestation is closely related to the etiological agent species [2,3]. Leishmaniasis is a disease that, depending on its severity, can cause lifelong scarring and deformity. The psychosocial burden of those affected may lead to social, aesthetic and psychological stigma [4]. Female sandflies of the genera Lutzomiya and Phlebotomus are the main vectors of leishmaniasis, transmitting the parasite through the bite in mammalian hosts, such as dogs, rodents and humans. The transmitted etiologic agents are the obligate intracellular protozoa of the genus Leishmania, and around 20 species have been reported as pathogenic to humans so far [5,6].
Although the life cycle of different species of Leishmania (Fig. 1) share common characteristics, it is important to emphasize that each has its own peculiarities. The interaction between an invertebrate vector (sandfly) and a vertebrate host (human, for instance) is vital for the complete digenetic cycle [7]. Multiple factors are related to the successfully establishment of the parasite in the host. Whereas the capacity of the host’s immune system is compromised and not responding properly, the parasite has the ability to evade or modulate this system by multiple mechanisms [8,9].
Initially, within the midgut of the sandfly, the flagellated forms of the parasite, promastigotes, go through several biochemical and morphological modifications (Fig. 1). These motile forms replicate and differentiate from the non-infective procyclic promastigotes to the infective metacyclic promastigotes [10]. The infection takes place when the sandfly regurgitates and innoculates the metacyclic promastigotes during a blood meal, wounding the skin and recruiting several types of phagocytic cells (macrophages, neutrophils and dendritic cells) to the site of the lesion [11]. The metacyclic promastigotes must surpass the extracellular matrix before being phagocytized. That is accomplished by various mechanisms which the parasite takes advantage, including the secretion of proteases that facilitates its penetration through the matrix [12]. Later on, the metacyclic promastigotes are promptly phagocytized by neutrophils, and then by macrophages [13,14]. After being internalized, the parasites establish within the macrophage’s phagolysosome a safe and nutrient filled environment to differentiate into amastigotes. These oval aflagellated forms replicate within the organelle via binary fission and, in order to survive this hostile environment, evade through several pathogenicity factors. Once the phagolysosome is unable to support the parasite load, rupture occurs and the amastigotes are released to be phagocytized over again [15,16]. An uninfected sandfly is required to take a blood meal containing amastigotes or infected phagocytes to complete the life cycle [17].
Current therapeutics on leishmaniasis is quite limited in terms of options available and with several drawbacks (Fig. 2) [18]. Antimonial-based drugs, such as stibogluconate 1 and N-methylglucamine antimoniate 2, are still the first-line treatment majorly in emerging and underdeveloped countries [19]. However, these toxic compounds present a variety of side effects and drug resistance is already a reality [19,20]. In fact, resistance for practically all clinically available drugs for leishmaniasis have already been reported, whether in vivo or in vitro [21]. The polyene amphotericin B 3 is highly effective for all clinical manifestations of leishmaniasis, although the high cost, nephrotoxicity and the need of extended hospitalization are clearly drawbacks [22]. The liposomal presentation of amphotericin B circumvents the toxicity issue, however its high cost persists to be its major limiting factor [22,23]. The only oral drug available for leishmaniasis is the alkylphosphocholine derivative miltefosine 4, possessing activity for both CL and VL. Gastrointestinal toxicity, along with vomiting, diarrhea and nausea, are recurring side effects. Additionally, teratogenicity prevents its use on pregnant women [22,24,25]. The aromatic diamidine pentamidine 5, presented as isethionate or dimesilate salt, is active against CL and VL. Irreversible insulin-dependent diabetes mellitus, myocarditis and nephrotoxicity are the most severe side effects associated to pentamidine [[26], [27], [28]]. Paromomycin sulfate 6 is an aminoglycoside with activity against VL and has synergistic effects with antimonials. Pain caused by its intramuscular administration is one of its drawbacks, besides nephrotoxicity and reversible ototoxicity [22,[28], [29], [30], [31]].
In light of these facts regarding to few clinically available options, several drawbacks of therapeutics and the complexity of the pathogenicity, it is imperative to search for new, safe, low cost and active compounds for leishmaniasis. As always, nature has proven to be a valuable source of bioactive compounds. Extracts and isolates of various classes have shown antileishmanial potential, including coumarins, the main focus of this review [32]. In the synthethic point of view, several classes of heterocycles are continuously being investigated by medicinal chemists, and coumarins indeed display an important role in this search for new antileishmanial agents [33,34].
The endless possibilities of functionalization and its unique features makes the coumarin 7 (Fig. 3) a privileged scaffold for medicinal chemists [35,36]. Whilst coumarins are majorly found as secondary metabolites in plants, bacteria and fungi, numerous methods have been reported to obtain coumarins synthetically. Composed by a benzene fused in a pyrone ring, this bicyclic heterocycle is capable to perform interactions with various biological targets [[35], [36], [37], [38]]. Hydrogen bonding with several amino acids residues is possible owing to the pyrone ring, whereas the aromatic portion has the ability to establish hydrophobic, π-π, CH-π and cation-π interactions [39]. As a result, such versatility translates into a vast range of biological properties, including antioxidant, anticoagulant, anticancer, antiviral, antitrypanosomal, anticholinesterase and also antileishmanial activities [[40], [41], [42], [43], [44], [45]].
Herein in this review, we will discuss the most relevant studies regarding antileishmanial coumarins published between 1997 and 2020. Both synthetic and naturally occurring coumarins will be covered in this review, along with a structure-activity relationship study of these compounds in each species of Leishmania discussed.
Section snippets
Natural coumarins
In this section, we will discuss about the naturally occurring coumarins with antileishmanial properties. As previously mentioned, coumarins occur as secondary metabolites in plants mainly from the families Rutaceae, Apiaceae, Asteraceae and Fabaceae. In general, coumarins are originated biosynthetically from the phenylpropanoid pathway. Numerous enzymes are related to the biosynthesis of different types of coumarins, leading to prenylated coumarins, linear and angular furanocoumarins,
Synthetic coumarins
It is notorious how such a small molecule as coumarin is capable to interact with a wide range of biological targets, although it is noteworthy to mention that the selectivity of these interactions are intimally related to its substitution pattern [35]. These features still attracts the interest of medicinal chemists, since the obtention of the coumarin nucleus synthetically is relatively simple, depending on the method employed [36]. A convenient method to obtain coumarins is the Pechmann
Structure-activity relationship studies
In this section, we will outline the design of some structure-activity relationship (SAR) studies of the reported coumarins against Leishmania. The structures were separated according to the following species, for the sake of clarity: (1) Leishmania major; (2) Leishmania braziliensis and Leishmania infantum; (3) Leishmania amazonensis; (4) Leishmania panamensis; and (5) Leishmania donovani. The Leishmania mexicana was disregarded due to the lack of structures for comparison. Some structures (73–
Author’s opinion
In this review, it became clear the urgency of new antileishmanial drugs, since current therapeutics is limited and outdated. Coumarins proved to be a promising scaffold to develop new antileishmanial agents, although limitations may be pointed out regarding some studies herein discussed. Leishmaniasis clinical manifestations are majorly responsible by the intracellular forms of the parasite - amastigotes. Thus, the absence of data relative to the activity against these forms limitate the
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors wish to thank the Brazilian funding agencies CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) for their financial support. Also, the authors would like to thank the graphic designer Fernanda Gularte Keller for the graphical abstract and life cycle illustrations.
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