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Background  The emergence of artemisinin-resistant  Plasmodium falciparum  strains poses a serious challenge to the control of malaria. This necessitates the development of new anti-malarial drugs. Previous studies have shown that the natural beta-carboline alkaloid harmine is a promising anti-malarial agent targeting the  P. falciparum  heat-shock protein 90 (PfHsp90). The aim of this study was to test the anti-malarial activity of harmine analogues.    Methods  Forty-two harmine analogues were synthesized and the binding of these analogues to  P. falciparum  heat shock protein 90 was investigated. The in vitro anti-malarial activity of two of the analogues, 17A and 21A, was evaluated using a 72-h growth inhibition assay. The in vivo anti-malarial activity was tested in  Plasmodium berghei  infection of BALB/c mice. The potential of 21A for a combination treatment with artemisinin was evaluated using in vivo combination study with dihydro-artemisinin in BALB/c mice. Cytotoxicity of the harmine analogues was tested in vitro using HepG2 and HeLa cell lines.    Results  17A and 21A bound to PfHsp90 with average IC 50  values of 12.2 ± 2.3 and 23.1 ± 8.8 µM, respectively. They also inhibited the  P. falciparum W2  strain with average IC 50  values of 4.2 ± 1.3 and 5.7 ± 1.7 µM, respectively. In vivo, three daily injections of  P. berghei -infected BALB/c mice with 100 mg/kg of either 17A or 21A showed significant reduction in parasitaemia with a 51.5 and 56.1% reduction, respectively. Mice treated with 17A and 21A showed a median survival time of 11 and 14 days, respectively, while the vehicle control mice survived a median of only 8.5 days. A dose-ranging experiment with 21A showed that the compound has a dose-dependent anti-malarial effect. Furthermore, treatment of infected mice with a combination of 21A and dihydroartemisinin (DHA) showed a dramatic reduction in parasitaemia compared to treatment with DHA alone.    Conclusion  A novel and non-toxic harmine analogue has been synthesized which binds to PfHsp90 protein, inhibits  P. falciparum  in vitro at micromolar concentration, reduces parasitaemia and prolongs survival of  P. berghei -infected mice with an additive anti-malarial effect when combined with DHA.

In vitro and in vivo anti-malarial activity of novel harmine-analog heat shock protein 90 inhibitors: a possible partner for artemisinin