Synthesis, cytotoxicity and antiplasmodial activity of novel ferrocenyl-artemisinin hybrids

Abstract

Malaria is caused by a parasite of the genus Plasmodium. Of the five species that infect humans, Plasmodium falciparum is the most dangerous. This disease caused 435 thousand deaths in 2017. It is estimated that 266 thousand of these deaths were children, under the age of five. With the reports of malaria resistance towards artemisnin, there is a desperate need for new and effective antimalarial drugs. In the search for these new antimalarial drugs, two series of artemisinin-ferrocene derivatives were prepared and investigated during this study. A mini-review (Chapter 3) was written in order to compare the most potent non-acetal artemisinin derivatives. In order to compare these derivatives, relative activity was used. Due to the large variety of Plasmodium falciparum strains used it is difficult to truly compare these derivatives. The general lack of toxicity data for these derivatives makes it difficult to establish whether the activity is due to toxicity. The logP value was calculated for these derivatives to be able to estimate toxicity. It was shown that there is some connection between lipophilicity and toxicity. The first series (Chapter 4) of amino-ferrocene-artemisinin derivatives was synthesized by the coupling of various mono-substituted ferrocene derivatives to 10α-(1′-piperazino)-10-deoxo-10-dihydroartemisinin (DHA-pip) through condensation and reductive amination. These derivatives were screened against the chloroquine-sensitive (CQ-sensitive) NF54 and chloroquine-resistant (CQ-resistant) K1 and W2 P. falciparum strains. Cytotoxicity was assessed against the Hek293 cell line while anticancer activity was assessed against the A375 cell line. The derivatives retained good antimalarial activity while being very selective towards parasitized cells in the presence of mammalian cells. Additionally these derivatives were in general more selective towards cancer cells in the presence of mammalian cells. The second series (Chapter 5) of amino-artemisinin-1, 2-disubstituted ferrocene derivatives was synthesized through reductive amination of aminoferrocenealdehydes to DHA-pip. These derivatives were screened against the CQ-sensitive NF54 and CQ-resistant K1 and W2 P. falciparum strains. Cytotoxicity was assessed against the Hek293 cell line while anticancer activity was assessed against the A375 cell line. These derivatives were also screened against P falciparum NF54 gametocytes. Two of these derivatives were more active than DHA while the activity of one of these derivatives might be attributed to toxicity. The least antimalarial active derivative was more active and selective towards cancer cells in the presence of mammalian cells. This study resulted in a number of derivatives with different antiplasmodial activities. The derivatives of series 2 were the most active due to the single ring disubstituted ferrocene derivatives. The derivatives that were synthesized during the study illustrate a low potential for resistance and addresses the problem of P. falciparum. These derivatives could potentially serve as lead compounds for future antimalarial drugs