Targeting Leishmania Fe-SOD and Glucose Metabolism with Tripodal and Pyridinacyclophane Polyamines as a Chemotherapeutic Strategy.

Background/Objectives: Many parasitic diseases remain without an effective treatment and cause many deaths worldwide. Leishmaniasis is a complex disease that belongs to the category of Neglected Tropical Diseases, as its treatment relies on outdated drugs that also lead to resistance and negative side-effects. To address this problem, two new chemical families have been tested in vitro against three of the most common parasites from the genus Leishmania. Methods: One family is formed by the polyamine tris(2-aminoethyl)amine functionalised either in one or its three primary amines with different aryl group, and the other is a group of azamacrocyclic cyclophanes containing either one or two aromatic spacers. Results: From the first family, only one compound showed activity against Leishmania donovani, and from the second family, three compounds were selective, two of them for Leishmania braziliensis and a different one against L. donovani, another parasite of the studied genus. Conclusions: The anti-Leishmania activity seems to be related to the compounds' ability to inhibit the iron superoxide dismutase activity and to alter the parasite metabolism by inhibiting glucose intake in L. braziliensis or by accelerating it in L. donovani and by attacking the parasite defences against ROS, both effects triggering a mitochondrial membrane depolarization that enhances damage, leading to cell death.