Promising natural products for the treatment of cutaneous leishmaniasis: A review of in vitro and in vivo studies

Leishmaniasis is an infectious disease caused by protozoa of the Leishmania genus. It is considered a neglected tropical disease by the World Health Organization, affecting 98 countries and with about 0.7–1 million cases annually (WHO, 2021, 2012), being a concern for health agencies worldwide. There are three major clinical forms of manifestation: visceral leishmaniasis (VL), mucocutaneous leishmaniasis (MCL), and cutaneous leishmaniasis (CL) (Davies et al., 2003; Desjeux, 2004; Dutta et al., 2006; Freitas-Junior et al., 2012; Matos et al., 2020a; Murray et al., 2005; No, 2016; Singh et al., 2012; Tiuman et al., 2011; Vijayakumar and Das, 2018; WHO 2021), which are classified according to the clinical aspects developed depending on the species of the infecting parasite. CL is the most common form and is usually characterized by the appearance of skin lesions in the area of the vector's bite (Carneiro et al., 2012; Dutta et al., 2006; Matos et al., 2020a; Matos et al., 2020b; Zulfiqar et al., 2017).

The treatments against leishmaniasis have limitations due to the emergence of parasite resistance, painful administration, and several adverse effects. The first-choice drugs used in the routine treatment of leishmaniasis (Fig. 1) are Meglumine antimoniate (Fig. 1a) and Sodium stibogluconate (Fig. 1b). The second-choice ones are amphotericin B (Fig. 1c) and pentamidine (Fig. 1d) (Alvar et al., 2006; Balaña-Fouce et al., 1998; Frézard et al., 2009; Goto, 2012; Goto and Lindoso, 2010; Matos et al., 2020a; Rocha et al., 2013; Singh et al., 2012; Soares et al., 2007; Sundar and Chakravarty, 2015). These treatments involve prolonged and costly therapies, serious adverse effects and toxicity, and variable efficacy, in addition to being parenterally administered (Alvar et al., 2006; Alvarenga et al., 2010; Balaña-Fouce et al., 1998; Croft et al., 2006; de Menezes et al., 2015; de Siqueira et al., 2017; den Boer et al., 2011; Freitas-Junior et al., 2012; Lima et al., 2015; McGwire and Satoskar, 2014; Pham et al., 2013; Rocha et al., 2013; Santos et al., 2008; Singh et al., 2012; Soares et al., 2007; Sundar and Chakravarty, 2015; Tiuman et al., 2011). All these mentioned factors contribute to poor patient compliance while increasing the risk of developing resistance (Aït-Oudhia et al., 2011; Álvarez-Bardón et al., 2020; Chakravarty and Sundar, 2010; Croft et al., 2006; Frézard et al., 2009; Ouellette et al., 2004; Partha, 2012; Ponte-Sucre et al., 2017; Rijal et al., 2013; Santos et al., 2008; Sundar and Olliaro, 2007), which is also a growing concern and one of the main causes of therapeutic failure, especially in endemic areas of the disease.

Based on this scenario, developing new, more effective, safe, and affordable leishmanicidal drug options for patients is necessary. For this purpose, many researchers have been betting on actives from natural products, being potential drug therapies, but also contributing to the synthesis and development of new drugs based on their chemical structures (Barreiro and Bolzani, 2009; Mishra and Tiwari, 2011; Nagle et al., 2014; Ndjonka et al., 2013; Newman and Cragg, 2012; Oliveira et al., 2013; Rocha et al., 2005; Singh et al., 2014). Natural therapy has been popularly used since ancient times until today for the treatment of various diseases, including leishmaniasis (Araújo et al., 2019; Bilbao-Ramos et al., 2020; Comandolli-Wyrepkowski et al., 2017; Fonseca-Silva et al., 2016; Gamboa-Leon et al., 2014; Gervazoni et al., 2018; Inacio et al., 2014; Kawakami et al., 2021; Kheirandish et al., 2016; Lezama-Dávila et al., 2016; Mahmoudvand et al., 2016; Mesa et al., 2017; Nieto-Yañez et al., 2017; Sharifi et al., 2021; Tiuman et al., 2012; Upegui-Zapata et al., 2020).

It is necessary to observe some steps for phytomedicine development, as shown in Fig. 2. The steps involve the entire process of harvest and botanical identification, extraction, purification, isolation and identification of the active molecule structure. The production of the extract or formulation containing the active ingredient, and the performance of in vitro and in vivo studies so that the drug can proceed to the clinical research. Natural products can offer a wide range of chemical diversity, which can be useful for developing new drugs with novel mechanisms of action. Many natural compounds have complex molecular structures that can be difficult to synthesize. The exploration of natural products for new therapeutic substances has the potential to offer a cost-effective and sustainable approach to drug discovery, particularly for neglected diseases like CL that have been historically underserved by pharmaceutical companies. (Buzanovsky et al., 2020; Grifferty et al., 2021; Okwor and Uzonna, 2016; Valero et al., 2021).

Based on the presented scenario, a review of articles about natural products as active sources for CL treatments was carried out, covering the period from January 2011 to December 2022. This review aims to select the articles that used plants as natural anti-leishmania actives and critically evaluate their quality to identify how to improve this study field. Also, this work aims to identify the natural products that present anti-leishmania effect to improve CL treatment.

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