In vitro antileishmanial activity and iron superoxide dismutase inhibition of arylamine Mannich base derivatives

Abstract

Leishmaniasis is one of the world's most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, we present 20 arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani and Leishmania braziliensis strains. Six out of the 20 Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy.

Tellurides Bearing Sulfonamides as Novel Inhibitors of Leishmanial Carbonic Anhydrase with Potent Antileishmanial Activity

“…The synthesized tellurides 5a− d and 5f were initially tested against Leishmania infantum axenic amastigotes according to the procedure previously described by our group by three independent experiments. 26,27 In order to assess the selectivity against L. infantum axenic amastigotes, the compounds were tested against leukemia cells derived from monocytes (THP-1). Miltefosine and edelfosine were used as reference drugs and the IC 50 obtained are summarized in Table 2.…”

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

“…Arylamine Mannich base derivatives, known to be effective against Trypanosoma cruzi, were exhibited remarkable activity against Leishmania species. The mechanism of action of these compounds was linked to their potent Fe-SOD inhibition [155].…”

Design and synthesis of Mannich base-type derivatives containing imidazole and benzimidazole as lead compounds for drug discovery in Chagas Disease

“…In addition, this group of compounds display other interesting biological activities, including analgesic, anti-bacterial, anti-cancer, anti-convulsant, anti-fungal, anti-inflammatory, antioxidant and anti-viral properties, among others [7,8]. Thus, Mannich bases represent promising alternatives to current anti-parasitic agents, due to their potential biological activity against parasites responsible for tropical diseases such as trypanosomiasis [9], leishmaniasis [10][11][12] and malaria [13][14][15][16]. Our group has continued this line of research via the incorporation of an array of amine fragments and substituents into the general structure of the Mannich bases [17][18][19][20], in an attempt to enhance their anti-chagasic and general anti-parasitic activity.…”