Imidazole-containing phthalazine derivatives inhibit Fe-SOD performance in Leishmania species and are active in vitro against visceral and mucosal leishmaniasis

Abstract

The in vitro leishmanicidal activity of a series of imidazole-containing phthalazine derivatives 1-4 was tested on Leishmania infantum, Leishmania braziliensis and Leishmania donovani parasites, and their cytotoxicity on J774·2 macrophage cells was also measured. All compounds tested showed selectivity indexes higher than that of the reference drug glucantime for the three Leishmania species, and the less bulky monoalkylamino substituted derivatives 2 and 4 were clearly more effective than their bisalkylamino substituted counterparts 1 and 3. Both infection rate measures and ultrastructural alterations studies confirmed that 2 and 4 were highly leishmanicidal and induced extensive parasite cell damage. Modifications to the excretion products of parasites treated with 2 and 4 were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds 2 and 4 were potent inhibitors of iron superoxide dismutase enzyme (Fe-SOD) in the three species considered, whereas their impact on human CuZn-SOD was low. Molecular modelling suggests that 2 and 4 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the antioxidant features of the enzyme.

In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives

“…This could view as a possible target for designing new molecules capable of acting on metal ion carried within their structure. [40][41][42] As a means of gaining more evidence in this regard, the effects exerted on T. cruzi Arequipa strain Fe-SOD by compounds 3, 4, 7 and 10 were assessed at concentrations of between 1 µM to 100 µM.…”

“…After removal of the drugs and nonphagocytosed parasites by washing, the infected cultures were grown in fresh medium for 10 day. 41 Every 48 h, fresh culture medium was added. The activity of the drugs was determined from the % of infected cells, the number of amastigotes per infected cell, and the number of trypomastigotes in the medium, both in treated as well as untreated cultures, and in methanol-fixed as well as Giemsastained preparations.…”

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…Tautomery can alter the skeleton of a given molecule, which in principle can be seen as a new distinct molecule with different complementarity to the target. Thus, Sanchez-Moreno et al studied the differences in activity against T. cruzi Fe-SOD enzyme of the possible tautomers of several imidazole derivatives [274][275][276][277][278].…”

Tropical and Subtropical Parasitic Diseases: Targets for a New Approach to Virtual Screening

“…In previous work, our research group synthesized phthalazine and benzo[ g ]phthalazine derivatives containing imidazole rings linked to the pyridazine rings through flexible alkylamine arms (Figure ). Remarkably, most of those compounds were more active in vitro against T. cruzi and less toxic against mammal Vero cells than the reference drug BZN . Furthermore, in vivo tests performed with the phthalazine derivatives on acute‐phase Chagas disease gave parasitemia inhibition values better than those of BZN, and a decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice .…”

“…In search of new effective anti‐parasitic drugs, different series of structures functionalized with nitrogenated heteroaromatic rings have been reported. Among them, different series of benzo[ g ]phthalazine and phthalazine derivatives functionalized with flexible side‐chains ending with pyrazole or imidazole moieties ( 1 – 10 ) have proved to show trypanosomicidal and leishmanicidal activity, being simultaneously powerful inhibitors of parasitic Fe‐SOD, and poorer inhibitors of human CuZn‐SOD.…”