Trypanocidal activity of tetradentated pyridine-based manganese complexes is not linked to inactivation of superoxide dismutase

Steverding, Dietmar, Kolosevska, Karolina and Sánchez-Moreno, Manuel (2018) Trypanocidal activity of tetradentated pyridine-based manganese complexes is not linked to inactivation of superoxide dismutase. Experimental Parasitology, 192. pp. 1-5. ISSN 0014-4894

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Two tetradentated pyridine-based manganese complexes (Cpd2 and Cpd3) were previously reported to inhibit efficiently the growth of Trypanosoma cruzi in vitro and in vivo. Cpd3 was also shown to be a potent inhibitor of trypanosomal iron superoxide dismutase (Fe-SOD) and its trypanocidal activity linked to the inhibition of this enzyme. Here we investigated the anti-trypanosomal activity of the two compounds against bloodstream forms of Trypanosoma brucei. Both compounds displayed potent trypanocidal activity against T. brucei bloodstream forms with minimum inhibitory concentrations (MICs) and 50% growth inhibition (GI50) values of 1 µM and 0.2-0.3 µM, respectively. Cpd2 and Cpd3 also showed cytotoxicity against HL-60 cells but based on GI50 values the human cells were 14 and 87 times less sensitive indicating moderate selectivity. In contrast to previous observation, Cpd3 did not inhibit Fe-SOD within trypanosomes and Cpd2 inhibited the enzyme only by 34%. As Fe-SOD together with ornithine decarboxylase play vital roles in the antioxidant defence in bloodstream forms of T. brucei, inhibition of both enzymes should be synergistically. Therefore, the interaction of Cpd2 and Cpd3 with the ornithine decarboxylase inhibitor eflornithine was determined. Both compounds were found in combination with eflornithine to produce only an additive effect. Thus, the observed lack of synergy between Cpd2/Cpd3 and eflornithine can be regarded as further indication that both compounds are not very strong inhibitors of trypanosomal Fe-SOD. Nevertheless, tetradentated pyridine-based manganese complexes are interesting compounds with promising anti-trypanosomal activity.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: LivePure Connector
Date Deposited: 18 Jul 2018 04:45
Last Modified: 22 Oct 2022 03:58
DOI: 10.1016/j.exppara.2018.07.005

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