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Fexinidazole (FEX) is a heterocyclic compound and constitutes the first 100% oral treatment drug for African trypanosomiasis. Its effectiveness against Trypanosoma brucei encouraged the investigation of its antiparasitic potential against T. cruzi, the aetiological agent of Chagas disease. Although previous studies addressed the antitrypanosomal effects of FEX, none used electron microscopy to identify the main target structures of T. brucei or T. cruzi. In this work, we used microscopy techniques to analyze the ultrastructural alterations caused by FEX in different developmental stages of T. cruzi. In addition to inhibiting T. cruzi proliferation, with IC 50 of 1 µM for intracellular amastigotes, FEX promoted massive disorganization of reservosomes, the detachment of the plasma membrane, unpacking of nuclear heterochromatin, mitochondrial swelling, Golgi disruption and alterations in the kinetoplast-mitochondrion complex. Together, these observations point to FEX as a potential drug leader for further developing of chemotherapy against Chagas disease., (© 2022. The Author(s).)

Kinetoplast DNA (kDNA) bearing unusual mitochondrion of trypanosomatid parasites offers a new paradigm in chemotherapy modality. Topoisomerase II of Leishmania donovani (LdTopII), a key enzyme associated with kDNA replication, is emerging as a potential drug target. However, mode of action of LdTopII targeted compounds in the parasites at sub-cellular level remains largely unknown. Previously, we reported that an isobenzofuranone derivative, namely 3,5-bis(4-chlorophenyl)-7-hydroxyisobenzofuran-1(3H)-one (JVPH3), targets LdTopII and induces apoptosis-like cell death in L. donovani. Here, we elucidate the phenotypic changes and the events occurring at sub-cellular level caused by JVPH3 in L. donovani. In addition, we have evaluated the cytotoxicity and ultrastructural alterations caused by JVPH3 in two brazilian trypanosomatid pathogens viz. L. amazonensis and Trypanosoma cruzi. Despite killing these parasites, JVPH3 caused significantly different phenotypes in L. donovani and L. amazonensis. More than 90% population of parasites showed altered morphology. Mitochondrion was a major target organelle subsequently causing kinetoplast network disorganization in Leishmania. Altered mitochondrial architecture was evident in 75-80% Leishmania population being investigated. Quantification of mitochondrial function using JC-1 fluorophore to measure a possible mitochondrial membrane depolarization further confirmed the mitochondrion as an essential target of the JVPH3 corroborating with the phenotype observed by electron microscopy. However, the impact of JVPH3 was lesser on T. cruzi than Leishmania. The molecule caused mitochondrial alteration in 40% population of the epimastigotes being investigated. To our knowledge, this is the first report to evaluate the proliferation pattern and ultrastructural alterations caused in Brazilian kinetoplastid pathogens by a synthetic LdTopII inhibitor previously established to have promising in vivo activity against Indian strain of L. donovani.