Highlights in Cysteine Protease Inhibitors as Antiparasitic Agents Against Trypanosomatids

Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp. are the causative agents of Chagas disease, human African trypanosomiasis, and leishmaniasis, respectively. These three neglected tropical diseases affect millions of individuals globally, and current therapeutic options remain severely limited. The major cysteine proteases (CPs) of these parasites play critical roles in their infectivity and survival, making them subjects of prolonged research. Therefore, cruzain, TbrCATL and CPB from Leishmania spp. have been recognized as the primary targets of most drugs under investigation. Among the diverse chemical classes investigated as cathepsin L-like inhibitors, natural compounds derivatives (including compounds derived from curcumin, Gallinamide A, and flavonoids) as well as molecules containing Michael acceptors, and nitrile and thiosemicarbazone moieties, have emerged as particularly promising scaffolds. The aim of this review is to provide an overview of the advances made over the last decade in the discovery and optimization of CP inhibitors with antitrypanosomal and antileishmanial activity, emphasizing their chemical scaffolds, biological activities, and therapeutic potential.