In vitro growth inhibition of bloodstream forms of Trypanosoma brucei and Trypanosoma congolenseby iron chelators

Abstract

African trypanosomes exert significant morbidity and mortality in man and livestock. Only a few drugs are available for the treatment of trypanosome infections and therefore, the development of new anti-trypanosomal agents is required. Previously it has been shown that bloodstream-form trypanosomes are sensitive to the iron chelator deferoxamine. In this study the effect of 13 iron chelators on the growth of Trypanosoma brucei, T. congolense and human HL-60 cells was tested in vitro. With the exception of 2 compounds, all chelators exhibited anti-trypanosomal activities, with 50% inhibitory concentration (IC 50 ) values ranging between 2.1 -220 µM. However, the iron chelators also displayed cytotoxicity towards human HL-60 cells and therefore, only less favourable selectivity indices compared to commercially available drugs. Interfering with iron metabolism may be a new strategy in the treatment of trypanosome infections. More specifically, lipophilic ironchelating agents may serve as lead compounds for novel anti-trypanosomal drug development.

Role of iron homeostasis in trypanosomiasis-associated anemia

“…In parallel, genes involved in iron metabolism including processing (HO-1, DMT-1), storage (FHC) and export/transport CP,Tf) are also significantly up-regulated and could contribute to increased iron storage or iron export or both. Increased Fe 2+ export (FPN-1) and extra-cellular conversion to Fe 3+ (CP) may be triggered during the rising phase of parasitemia to sustain high levels of Tfassociated Fe 3+ as a possible requirement for optimal parasite development (Merschjohann and Steverding, 2006;Schell et al, 1991), since trypanosomes express a Tf-R (Grab et al, 1993). (ii) During the second phase of anemia that parallels the chronic phase of infection, the increased expression of genes contributing to erythrophagocytosis (Fcg-R, CD36) and/or uptake of ironcontaining compounds (CD91, Tf-R1) is maintained as well as genes involved in iron processing and storage.…”

Trypanosoma brucei transferrin receptor can bind C-lobe and N-lobe fragments of transferrin

“…As for most living organisms iron is essential for the viability of bloodstream forms of T. brucei [1,2]. Iron is provided by the host and is delivered to the circulating trypanosomes as a complex with host transferrin (Tf) [3,4].…”

The umpolung of substituent effect in nucleophilic aromatic substitution. A new approach to the synthesis of N,N-disubstituted melamines (triazine triskelions) under mild reaction conditions

“…3 As potent cytotoxic agents targeting the G2/M phase of the cell cycle, 4 inhibitors of phosphatidylinositol 3-kinase, 5 matrix metalloproteinase, 6 tyrosine kinase, 7 and inhibitors of angiogenesis, 8 melamine derivatives are some of the most promising anticancer, 9 antiviral, antitripanozoma, 10 and antiprotozoal agents.…”