Development of novel agents against parasitic diseases

The World Health Organization (WHO) recognizes 17 major parasitic diseases as the neglected topical diseases (NTDs). Despite positive advances over the past decade, the NTDs continue to rank among the world’s greatest global health problems affecting more than 1 billion people worldwide. Available drugs, vaccines, diagnostic and vector control technologies have a limited use because of their toxicities, inadequate efficacies, emerging antimicrobial resistance or because they do not prevent reinfection. Thus, new therapeutic products are urgently required. In this work, the study of natural compounds as lead compounds for the future development of antiparasitic agents (malaria and human african trypanosomiasis) is presented. Among the parasitic diseases, malaria remains the most significant in the tropics where it causes from 200 to 300 million new cases every year, leading to an estimated 445 000 deaths (world malaria report 2017). Malaria is caused by protozoan parasites of the genus Plasmodium, of which the most lethal species is P. falciparum and transmitted by blood-feeding female mosquitoes, the vector of the parasite. Artemisinin, an endoperoxide-based compound, and its semisynthetic derivatives, used in combination with other antimalarial drugs (Artemisinin-based Combination Therapies or ACT), are the preferred treatment for malaria. However, the low bioavailability, the short half-life, the high cost of these drugs and the emergence of resistance (detected in five countries) are a major drawback of their use. In this thesis, the design and the preparation of synthetic analogues of 9,10-dihydroplakortin (DHP), a natural product characterized by a cyclic peroxide moiety with interesting antimalarial activity, is described. By modifying and gradually simplifying the complex structure of DHP, a new series of antimalarial endoperoxides endowed with a simple bridged bicyclic system was developed. The straightforward way to synthetize them (a high-yielding three-steps protocol) allowed the decoration of the bicyclic core with several functionalized chains, allowing to explore the structure-activity relationships (SARs) and analyze their binding mode to the target of peroxides, namely the free Fe(II)-heme. Human African Trypanosomiasis (HAT or sleeping sickness) is a parasitic disease transmitted by the tsetse fly and caused by two subspecies of Trypanosoma brucei: T. brucei rhodesiense and T. brucei gambiense. HAT occurs regularly in specific rural areas of sub-Saharan Africa with the population at risk being about 70 million in 36 countries. The available drugs are few, old, toxic and complicated to administer. The furanoheliangolide 4,15-isoatriplicolide tiglate, isolated from Heliantus schweinitzii (Asteraceae), was recently discovered as an extremely potent trypanocidal agent with an in vitro IC50 of only 15nM against T. brucei rhodesiense. The interesting pharmacological properties of this natural compound and its low availability from natural sources prompt us to develop a total synthesis of this promising antiparasitic hit compound. The approach here described focused on the development of different strategies for the preparation of key macrocyclic intermediates for its synthesis. In particular, three synthetic approaches were investigated allowing to understand the chemical reactivity of the examined systems.