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Background  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.    Methods  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.    Results  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 (IC 50  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.    Conclusion  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.    Electronic supplementary material  The online version of this article (10.1186/s12936-018-2281-x) contains supplementary material, which is available to authorized users.

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