In vitro and in vivo anti-malarial activity of novel harmine-analog heat shock protein 90 inhibitors a possible partner for artemisinin.
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. 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 BALBc mice. The potential of 21A for a combination treatment with artemisinin was evaluated using in vivo combination study with dihydro-artemisinin in BALBc mice. Cytotoxicity of the harmine analogues was tested in vitro using HepG2 and HeLa cell lines. 17A and 21A bound to PfHsp90 with average IC 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.