**Metal-Based Therapeutics for Leishmaniasis**

Ana B. Caballero, Juan M. Salas and Manuel Sánchez-Moreno

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57376

**1. Introduction**

#### **1.1. Metal-based drugs and their growing application to the treatment of parasitic diseases**

When we speak of metals in medicine, many of us still associate them almost unconsciously with toxic rather than curative effects. However, despite the known toxic effect of some metal ions in humans, many metal ions (in adequate dosages) are required for many critical functions in our organism. Scarcity of some of them even can lead to a disease. Well-known examples include anemia resulting from iron deficiency, growth retardation arising from insufficient zinc, and heart disease in children owing to copper deficiency.

Metals have been used for medicinal purposes since ancient times. The earliest evidence of their therapeutic application has been dated back to 1500BC in Ebers Papyrus, Egypt. Among 700 magical formulas and remedies, this ancient manuscript describes the use of copper to reduce inflammation and the use of iron to treat anemia. Later on, the alchemical practice in the Middle Age made a significant use of metals like gold or arsenic to prepare medicinal compounds and elixirs. In the 16th century, antimony was introduced by Paracelsus as a general panacea and was considered as one of the Seven Wonders of the World.

In the early 20th century, the physician Paul Elhrich (Nobel Prize 1908) discovered an impresive therapeutic effect of the compound arsenophenylglycine to treat sleeping sickness (Trypano‐ soma disease) and developed the first effective medicinal treatment for syphilis, also arseniumcontaining drug Arshphenamine, which was commercialized under the name Salvarsan. The concept of chemotherapy was born. At this time, other metallodrugs appeared. Sodium vanadate and derivatives of bismaltolato oxovanadium(IV) complexes started to be applied to lower levels of blood sugar in diabetic patients, and gold(I) complexes such as Auranofin, sodium aurothiomalate and aurothioglucose were prescribed to treat rheumatoid arthritis

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(Figure 1). In 1987, sodium aurothiomalate was also used to treat 10 patients with kala-azar and showed an excellent clinical response.[1]

**Figure 1.** Gold-based drugs most commonly used for the treatment of rheumatoid arthritis. Sodium aurothiomalate has also shown chemotherapeutic effect against kala-azar.

Despite these early demonstrations of the potential of metals to treat diseases, organic drugs have traditionally dominated modern medicinal chemistry and pharmacology. It was the serendipitous discovery in 1969 of the anticancer properties of cisplatin, a Pt(II) complex, which propelled dramatically the research on metal ions in modern medicine until nowadays, not only in therapy but also in diagnosis. Examples of the latter are radiolabeling of compounds with 99mTc for X-ray imaging and use of Gd(III) complexes as MRI agents. Moreover, this event marked the change from an empirical discovery into a rational design of new metallodrugs and the consequent development of medicinal inorganic chemistry as a mature research discipline.

The increasing interest in the research of metal compounds with potential applications in medicine along the last decades has come along to a deeper understanding of the reactivity of metal ions and their interaction with a wide range of biomolecules such as DNA and proteins. [2] Scientific community has realized that either coordination or organometallic chemistry offer wide possibilities to develop novel metal-based drugs bearing quite different mecha‐ nisms of action aiming at different targets.

The dramatic incidence and economic impact of cancer diseases in modern world and especially in developed countries has led research on medicinal inorganic chemistry (and still is) to focus mainly on development of antitumoral compounds of different metals. This includes their design to specifically attack cancer cells and interact directly with DNA, with protein active sites or with smaller biomolecules of key importance in cancer development, as well as improving their biodistribution. As a result, a number of metal complexes with antitumoral potential have been developed in the last years, mostly of platinum and rutheni‐ um, and some of them have provided excellent results. In fact, drugs like oxaliplatin are currently used to treat colorrectal cancer. Moreover, the antimetastatic drug NAMI-A is under the last phase of clinical evaluation.

On the other hand, a comparatively smaller progress has been made in the discovery of new metal compounds to treat tropical parasitic diseases, which has been mostly based on an empirical use. Various inorganic salts have been administered against the major tropical diseases, sometimes with very good results.

(Figure 1). In 1987, sodium aurothiomalate was also used to treat 10 patients with kala-azar

**Figure 1.** Gold-based drugs most commonly used for the treatment of rheumatoid arthritis. Sodium aurothiomalate

Despite these early demonstrations of the potential of metals to treat diseases, organic drugs have traditionally dominated modern medicinal chemistry and pharmacology. It was the serendipitous discovery in 1969 of the anticancer properties of cisplatin, a Pt(II) complex, which propelled dramatically the research on metal ions in modern medicine until nowadays, not only in therapy but also in diagnosis. Examples of the latter are radiolabeling of compounds with 99mTc for X-ray imaging and use of Gd(III) complexes as MRI agents. Moreover, this event marked the change from an empirical discovery into a rational design of new metallodrugs and the consequent development of medicinal inorganic chemistry as a mature research

The increasing interest in the research of metal compounds with potential applications in medicine along the last decades has come along to a deeper understanding of the reactivity of metal ions and their interaction with a wide range of biomolecules such as DNA and proteins. [2] Scientific community has realized that either coordination or organometallic chemistry offer wide possibilities to develop novel metal-based drugs bearing quite different mecha‐

The dramatic incidence and economic impact of cancer diseases in modern world and especially in developed countries has led research on medicinal inorganic chemistry (and still is) to focus mainly on development of antitumoral compounds of different metals. This includes their design to specifically attack cancer cells and interact directly with DNA, with protein active sites or with smaller biomolecules of key importance in cancer development, as well as improving their biodistribution. As a result, a number of metal complexes with antitumoral potential have been developed in the last years, mostly of platinum and rutheni‐ um, and some of them have provided excellent results. In fact, drugs like oxaliplatin are currently used to treat colorrectal cancer. Moreover, the antimetastatic drug NAMI-A is under

and showed an excellent clinical response.[1]

466 Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment

has also shown chemotherapeutic effect against kala-azar.

nisms of action aiming at different targets.

the last phase of clinical evaluation.

discipline.

The best-known example is a series of antimony compounds such as sodium stibogluconate (Pentostam) and meglumine antimoniate (Glucantime). These compounds were developed more than 60 years ago and still constitute the treatment of choice for some forms of leishma‐ niasis. However, antimonial-based treatments usually present toxicity problems, limited efficacy and emerging resistance. This leads scientists to explore other metal ions in search of improved therapies. In addition no structure-function correlation studies have yet been performed on antiparasitic metal-based compounds. These arguments open the way to new mechanistic investigations in this research area for optimization of the identified metal leads and development of new ones.

But what can metals offer towards improved antiparasitic therapies? Metal ions offer a wide range of coordination numbers and geometries, redox states, and thermodynamic and kinetic characteristics. This, along with the possibility to rationally combine the intrinsic properties of a metal ion with a bioactive ligand/s bearing therapeutic interest, provides innumerable possibilities for drug design and an extremely wide spectrum of therapeutic activity not readily available to organic compounds.

One of the most used design approaches is grounded in the metal-drug synergism that results from the attachment of a metal moiety to the structure of an organic drug. [3] This synergy gives rise to two main effects:


The work of Williamson and Farrell in 1976 was the first in applying and demonstrate this concept for a tropical disease, trypanosomiasis. [4]

Among other illustrative examples of this approach, it should be mentioned the ferroquine (FQ), in which insertion of a Fe(II) ion in the form of ferrocene into the scaffold of the antima‐ larial drug chloroquine enhanced the pharmacology of the drug. [5] FQ is being developed by Sanofi-Aventis and entered phase II clinical trials in September 2007. Other example is a ruthenium(II) complex with the antitrypanocidal compound benznidazole, *trans*-[Ru(Bz) (NH3)4SO2](CF3SO3)2, which shows higher hydrosolubility and activity than the free antipar‐ asitic drug. [6] (Figure 2)

Other advantages of using metal compounds are their pronounced selectivity for selected parasites biomolecules compared to the host biomolecules,[7] and the possibilities they offer to targeted therapies as targeting molecules may be reversibly appended and prodrugs can be developed to deliver highly reactive metal specia in the parasite target while minimising nonspecific interactions.

In the last years, nanotechnology has revolutioned the medicine field by opening novel and promising approaches for drug design, in particular regarding use of nanoparticles (1-100 nm) as drug delivery vehicles. Despite being liposomes and polymeric particles the most investi‐ gated systems to deliver antiparasitic drugs, metal nanoparticles have also emerged as interesting alternative carriers. [8] Furthermore, use of nanoforms of antiparasitic metals like antimony and selenium as alternatives to molecular forms [9,10] has also been recently reported.

In summary, there is a clear need for research in this largely neglected area of medicinal chemistry that is tropical parasitic diseases, and use of metal complexes as possible chemo‐ therapeutic agents arises as a very attractive alternative to tackle this immense problem. However, despite the obvious potential of metal complexes as diagnostic and chemothera‐ peutic agents, few pharmaceutical or chemical companies have serious in-house research programs that address these important bioinorganic aspects of medicine, which contrast tremendously with the case of purely organic drugs.

The following sections will focus on diverse examples of metal compounds with current or potential applications for leishmaniasis treatment.
