New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

• DOI: 10.1186/s12936-018-2281-x
• Publication Date: 2018-04-03T23:49:12Z
• Authors: Lis Lobo; Lília I. L. Cabral; Maria Inês Sena; Bruno Guerreiro; António Sebastião...; Valter Ferreira d...; Maria L. S. Crist...; Fatima Nogueira
• Keywords: RC955-962; Plasmodium falciparum; Tetraoxane–tetrazole conjugates; Drug Resistance; Trioxolane-tetrazole conjugates; Trioxolane–tetrazole conjugates; Tetraoxane-tetrazole conjugates; Infectious and parasitic diseases; RC109-216; Diamines; Antimalarials; Mice; 03 medical and health sciences; Cricetulus; Arctic medicine. Tropical medicine; Animals; Humans; Antimalarial drug resistance; Benzothiazoles; In vivo antimalarial activity; Organic Chemicals; 0303 health sciences; Research; Hep G2 Cells; Artemisinins; Peroxides; 3. Good health; Quinolines

The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs.A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay.The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3-71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration.The investigated, trioxolane-tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.