Drug Discovery and preclinical Development for Human and Animal African Trypanosomiasis: Profiling of a collection of Natural Compounds with ADME-(Eco)Toxicity properties

Human African trypanosomiasis (HAT), also known as sleeping sickness, and Animal African trypanosomiasis (AAT) are life-threatening neglected tropical diseases generally caused by the Trypanosoma brucei subspecies. HAT represents a critical public health issue in 36 African countries, with approximately 65 million people at risk, predominantly affecting impoverished communities in sub-Saharan Africa, where it poses a significant health and economic burden 1 . AAT, similarly, affects livestock, leading to severe economic losses due to decreased productivity and increased mortality in affected animals. Despite advances in reducing HAT cases and improving treatments, AAT remains a reservoir of infection, making its control crucial as part of the One Health approach. Current treatments, including suramin, pentamidine, melarsoprol, eflornithine, and the recent nifurtimox-eflornithine combination therapy, are associated with several drawbacks, like toxicity, high cost, and emerging drug resistance 2 . Given these limitations, there is an urgent need for new, effective and safe trypanocidal drugs. Natural products, with their unique chemical structures and bioactivity, represent a promising resource for drug discovery 3 . However, information on natural compounds with trypanocidal activity is often fragmented, with existing reviews typically focusing on a single class of molecules and often outdated. Establishing a comprehensive database of natural candidates with proven trypanocidal activity is crucial to identify promising scaffolds and accelerate the discovery of new hits/leads. The database built in this work includes relevant data on natural compounds active against T. brucei, incorporating literature data from 2019 to 2024, with their chemical structure, biological activity, cytotoxicity and, when described in the literature, molecular target/s. By systematically classifying natural products with anti-trypanosomal properties, this database, properly integrated with ADME and ECOTOX parameters, represents a first crucial step to disclose new effective treatments for both HAT and AAT, thus significantly contributing to the global effort to control and eradicate trypanosomiasis.