Recent Advances in the Synthesis of Organic Compounds to Combat Neglected Tropical Diseases

Chagas disease was discovered over 100 years ago, and continues to be a major public health problem, with 16 to 18 million people infected with Trypanososma cruzi, its causative agent, and 21,000 deaths associated with this disease every year. Nifurtimox (Nfx) and benznidazole (Bnz) are even today the only clinically available drugs for the chemotherapy of Chagas disease, but they show significant side effects, involve long-term treatment and there are other problems, like emergence of resistant strains. This chapter aims to highlight recent contributions from the organic synthesis field on developing new compounds with trypanocidal activity, including discussion on important structural features and molecular targets.

Dengue fever (DF) is the most important mosquito-borne viral disease, affecting around 100 million people mainly in tropical and subtropical countries. The dengue virus (DENV) is a member of the Flaviviridae family and possesses a single positive-stranded RNA genetic material encoding a single polyprotein, which is cleaved into structural and nonstructural proteins. The consequences of DENV infections range from fever to haemorrhagic manifestations, and the treatment of the disease is restricted to symptomatic relief. Medicinal chemistry approaches allied with synthetic methods can be of great importance for developing effective treatment for this disease, and the scientific literature provides interesting results of studies that mainly targeted viral processes to give rise to novel drugs. Viral entry, RNA replication, and polyprotein cleavage have been the main, although not the only, focus in the development of novel anti-viral compounds for the prevention and treatment of DF. In this chapter, we focus on the new trends in the development of bioactive small molecules.

Leishmaniasis is considered by the World Health Organization to be one of the world’s most neglected diseases. The current drugs used to treat leishmaniasis were developed more than 40 years ago and are toxic. In addition, they generate resistance, and coinfection with the AIDS virus has worsened the situation of this disease. The purpose of this chapter is to review the various synthetic compounds described between 2002 and 2012 that have been tested against Leishmania spp. and that could be considered possible prototypes for treating this disease. Compounds were organized into 20 chemical classes.

Leprosy is still considered one of the world’s important chronic diseases. Although multidrug therapy (MDT) has contributed to decline of its incidence, there are still hundreds of thousands of new cases each year. A full understanding of the physiological, clinical, transmission, immunology, genetic and bacterial aspects of this disease is very important to track the problem by multidisciplinary scientific investigation. Excellent work on the design and synthesis of new drugs to treat Leprosy is being performed all over the world, and is included in this manuscript. Nevertheless, studies to find more effective drugs to treat leprosy are still needed. Leprosy and others parasitic, bacterial, viral and protozoan infections form the group of neglected tropical diseases (NTD) and are among the leading causes of chronic disability and poverty in low- and middle-income countries.

Lymphatic filariasis (LF) is one of the most devastating neglected diseases in terms of social and economic impact, disabling and disfiguring infected individuals. The infection occurs by parasitic filarial nematode worms that are transmitted between humans by blood-sucking insects. These parasites are known to have affected individuals in 81 countries, mostly in developing areas. Despite the epidemiological importance of this disease, current therapies have low effectiveness and a combined therapy has been adopted as the standard treatment. To interrupt transmission, the WHO recommends an annual mass drug distribution in endemic areas; however, this annual mass drug distribution program has resulted in an increase in nematode resistance. This type of program also depends on the availability of the required drugs, such as diethylcarbamazine, ivermectin, and albendazole. Some aspects of the production of these drugs are described in this chapter. Although clinically well characterized, there is an urgent need for innovative drugs for the treatment of neglected tropical diseases, and recent findings from structural chemistry studies could lead to safe, effective, and lowcost treatments for LF infection.

Malaria is a tropical disease caused by infectious species of Plasmodium that are transmitted to people through the bites of infected mosquitoes. Malaria kills more than 650,000 people worldwide each year. Plasmodium resistance to antimalarial medicines, toxicity and high cost are the major obstacles in the fight against this disease. Therefore, there is an urgent need for the development of new more effective and less toxic antimalarials, especially compounds that act against novel molecular targets in order to circumvent the problem of increasing resistance. This chapter is focused on recent advances in the field of synthesis of compounds having antimalarial activity based on two strategies: synthesis of hybrid molecules and synthesis of inhibitors of a cysteine protease (falcipain) that plays a key role in malaria parasites.

Parasitic infections affect a vast number of people around the world. Schistosomiasis is a known example of tropical parasitic disease. Since the past decade, an increasing effort has been made towards its control. There are two main chemical interventions employed to cut off the schistosomiasis life-cycle. The first one consists of therapy, to treat infected individuals. The second uses molluscicidal compounds to control the population of the vector snails. This latter strategy has been considered as one of the best preventive actions, since it eliminates the parasites before they can reach human hosts. Towards this end, synthetic molluscicide, niclosamide, has proved to have efficient activity against schistosomiasis. Nevertheless, undesirable side effects associated with this compound, such as toxicity to non-target organisms in the aquatic environment, encouraged the search for new molluscicidal compounds. Although synthetic drugs often display higher molluscicidal activity than natural products, their lack of selectivity towards nocive snails, as well as difficult biodegradation, cause severe burdens on the environment. This problem has caused criticism on the use of the currently available synthetic molluscicides and turned the interest of a part of the scientific community to the investigation of new compounds, including natural substances. In fact, the dilemma between synthetic and natural products is not yet settled, and it still remains a challenge to find an effective and eco-friendly substance to combat the snails selectively. The focus of this chapter is to present an overview of recent studies on synthetic compounds and natural products with molluscicidal activity.

Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (MTB) bacteria that is both preventable and curable. Although the mortality rate has decreased worldwide, the emergence of multidrugresistant MTB, extensively drug-resistant MTB, and MTB/human immunodeficiency virus are stifling attempts to control TB and are associated with high rates of morbidity, mortality, and impoverishment worldwide. Although the investment in research and development has grown in recent years, the development of new candidate drugs has not increased proportionally. Nevertheless, in the last few years we have seen some evolution in the development of antitubercular drugs. After a gap of over 50 years without any new drugs, several candidate drugs have been developed, offering new hope for the treatment of drug-resistant strains of TB. Instead of focusing on recently approved drugs or drugs close to approval, the objective of this review is to describe the recent advances in the organic synthesis of drugs in early stages of development (hit-tolead) that have shown good results in vitro in terms of the minimum inhibitory concentration, median inhibitory concentration, and selectivity index.