Leishmaniasis are diseases caused by trypanosomatid protozoan parasites from the genus Leishmania, transmitted by insects from the genus Phlebotomus (World Health Organization, 2021). Clinical manifestations go from cutaneous lesions, with potential dissemination to mucoses, until complicated visceral forms which could produce death if untreated (Lamotte et al., 2019). The illness harshness depends on the Leishmania species, among other factors (Hussain et al., 2014). Leishmania donovani and L. infantum are responsible for visceral leishmaniasis, a systemic infection involving the liver, spleen and bone marrow, as well as chronic wasting, anemia and hepatosplenomegaly. Visceral leishmaniasis (or kala-azar) exhibits a high mortality without treatment. Mucocutaneous and cutaneous leishmaniasis imply skin and mucosal damages of different severity (Field et al., 2017).

Leishmaniasis is present in around 98 countries, with 700,000–1 million new cases in a year (World Health Organization, 2021). Transmition occurs by the insect saliva and invation of host monocytes and macrophages. Parasite replication occurs in parasitophorous vacuoles. The infective insect stage is metacyclic promastigote, inoculated in the human blood. Promastigotes invade diverse cells, mainly macrophages, in which they transform to replicating amastigotes. Insect takes promastigotes in a blood meal from an infected person, and parasite replicates and differentiates in the invertebrate to metacyclic promastigotes (Field et al., 2017).

In the absence of efficient strategies to control reservoirs and vectors, as well as preventive and therapeutic human vaccines, the current intervention strategy to limit the disease is chemotherapy, mainly with pentavalent antimonial compounds, amphotericin B, paromomycin, pentamidine and miltefosine (Bhat et al., 2018; Lamotte et al., 2019; Olías-Molero et al., 2021). Therapies for leishmaniasis are mainly based on repurposing drugs, including antifungal (amphotericin B), anticancer (miltefosine) and antibiotical (paromomycin) drugs (Shakya et al., 2011; Charlton et al., 2018). However, current treatments are limited and inconvenient, including a high cost for low and middle-income countries, a restrictive administration mode (Welay et al., 2017), toxicity (Sundar and Chakravarty, 2010), treatment failed and drug resistance (Ponte-Sucre et al., 2017). This alarming situation and the low amount of available new therapeutic molecules, determine the urgent necessity to search new pharmacological compounds/targets to control this disease (Mohapatra, 2014).

Taking into account the structural and functional diversity of the antileishmanial compounds, in this work we discuss the potentialities of several natural or synthetic compounds as new drugs, validated or in process. The selection of compounds presented here is based on their in vitro and in vivo activity, as well as on their known mechanism of action. The discussion is restricted to preclinical level, and the compounds are presented organized by their chemical nature, source and molecular targets. To review the molecular targets of antileishmanial compounds, see the work of Istanbullu and Bayraktar (2022). On the other hand, a detailed analysis of the current bottlenecks and their solutions in drug discovery and development in leishmaniasis, is presented in the review of Olías-Molero et al. (2021).