**1. Introduction**

Leishmaniasis is a neglected tropical disease that comprises a large and complex group of infections caused by the *Leishmania* genus protozoan parasites. *Leishmania* parasites have intrinsic biological features that make chemotherapy challenging, presenting high adaptability and plasticity. Its life cycle has two different developmental stages: intracellular amastigotes that live in the mammalian host cells and promastigotes that develop in the insect vectors (**Figure 1**) [1].

**Figure 1.**

*Illustration of the amastigote (left) and promastigote (right) forms of* Leishmania *sp. showing the main organelles and structures.*

The ultrastructure of *Leishmania* parasites (**Figure 2**) presents some conserved features and a classical internal organization of eukaryotic cells, with an individualized nuclear envelope, a single and ramified mitochondrion, endoplasmic reticulum, and Golgi complex, which can lead to difficulties in the development of *Leishmania*-specific drugs with low toxic side effects to mammalian hosts [1]. In addition, however, these protozoans have essential and exclusive organelles and structures such as acidocalcisomes, glycosomes, megasomes, and subpellicular microtubules (**Figure 1**) that can be exploited as drug targets [2].

The *Leishmania* plasma membrane comprises a lipid bilayer associated with proteins and a glycocalyx consisting of a myriad of glycoconjugates. The lipid bilayer has a trilaminar aspect with about 9 nm of thickness. The lipidic composition of the Trypanosomatidae family members is dependent on genus and species. In general, *Leishmania* has 24-methylated sterols, such as episterol, 5-dehydroepisterol, and traces of ergosterol as the major endogenous sterols' constituents, which are absent in mammalian host cells, where cholesterol is the main source of membrane sterols [3]. This divergence in sterol profiles has been exploited to develop drugs that affect the sterols biosynthesis pathway, including azoles,

#### **Figure 2.**

*Ultrathin sections of* L. amazonensis *amastigotes (A) and promastigote (B). F, flagellum; HC, host cell; K, kinetoplast; LB, lipid body; M, mitochondrion; N, nucleus.*

#### *Use of Cell Biology to Identify Cellular Targets in Drug Development Process... DOI: http://dx.doi.org/10.5772/intechopen.101662*

azasterols, and others [2]. In addition, many attempts to develop drugs targeting *Leishmania* glycocalyx have also been performed [4].

*Leishmania* parasites present a single and ramified mitochondrion frequently associated with the plasma membrane, subpellicular microtubules, and endoplasmic reticulum. As well as in other eukaryotes, *Leishmania* mitochondrion operates in energetic metabolism, compartmentalizing the Krebs cycle and performing cellular respiration. The amphotericin B and pentamidine, two of the currently used drugs for the treatment of leishmaniasis, target mitochondria, resulting in a decrease of the mitochondrial membrane potential. Moreover, other drugs targeting mitochondria, such as hydroxynaphthoquinones, have been evaluated against *Leishmania* [5].

To maintain its morphological structure, *Leishmania* has a cytoskeleton composed mainly of subpellicular microtubules, which are filaments finely associated to plasma membrane inner leaflet, regularly spaced, and longitudinally oriented throughout the parasite's cellular body. Despite the phylogenetic conservation of α and β-tubulins, structural divergences in specific tubulin drug binding sites have suggested these proteins as a potential target, as described for podophyllotoxin derivatives and others [6, 7].

In the Medicinal Chemistry field, several approaches have been attempted, trying to find potential cellular targets for developing anti-*Leishmania* drugs. First, nanotechnology-based drug delivery systems have been applied, improving efficacy and enhancing pharmacokinetics properties of currently available drugs [8]. Second, molecular hybridization techniques can combine two drugs or chemical groups with previously known biological activity, producing a single and novel molecule with increased activity [9]. Finally, another alternative is the transposition of a drug already used to treat another disease; it is the case of miltefosine, the last treatment included in the arsenal of chemotherapeutic agents against leishmaniasis. Miltefosine was initially designed as an anticancer medicine, and in 2002 it was registered as first-line treatment, mainly for visceral leishmaniasis (VL), in Asia, Africa, and some regions of Europe.
