Novel Agents against Human African Trypanosomiasis: Updates on Medicinal Chemistry and Target Identification

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Also known as sleeping sickness, human African trypanosomiasis (HAT) is caused by protozoan parasites of the genus Trypanosoma transmitted between humans by the bites of tsetse flies (glossina). HAT is caused by two parasite subspecies - Trypanosoma brucei gambiense (accounting for 92% of reported cases and causes chronic illness) and Trypanosoma brucei rhodesiense (accounting for 8% of reported cases and is responsible for the acute form of the disease). The former can advance, affecting the central nervous system, while the latter can develop rapidly with multiple organs, including the brain, being invaded. If left untreated, HAT is generally fatal. According to the World Health Organization, in the period 2016 – 2020, about 55 million people were at risk of infection, with nearly 1000 cases reported in 2018. Current treatment options have limitations such as complex administration procedures, limited effectiveness, emergence of drug resistance, and undesirable side effects. Therefore, new drugs are required. In this book chapter, we summarize current efforts aimed at identifying new drug candidates and their corresponding mechanisms of action. We highlight medicinal chemistry optimization efforts for different candidates while giving detailed insights into the mechanism of function for the corresponding drug targets. Such information is of value as it equips drug discovery scientists with information about chemical modifications, which can lead to improvement in certain physicochemical and biological properties of new chemical entities.