Abstract
We have demonstrated previously that amino-artemisinins including artemiside and artemisone in which an amino group replaces the oxygen-bearing substituents attached to C-10 of the current clinical artemisinin derivatives dihydroartemisinin (DHA), artemether and artesunate, display potent activities in vitro against the asexual blood stages of Plasmodium falciparum (Pf). In particular, the compounds are active against late blood stage Pf gametocytes, and are strongly synergistic in combination with the redox active drug methylene blue. In order to fortify the eventual selection of optimum amino-artemisinins for development into new triple combination therapies also active against artemisinin-resistant Pf mutants, we have prepared new amino-artemisinins based on the easily accessible and inexpensive DHA-piperazine. The latter was converted into alkyl- and aryl sulfonamides, ureas and amides. These derivatives were screened together with the comparator drugs DHA and the hitherto most active amino-artemisinins artemiside and artemisone against asexual and sexual blood stages of Pf and liver stage P. berghei (Pb) sporozoites. Several of the new amino-artemisinins bearing aryl-urea and -amide groups are potently active against both asexual, and late blood stage gametocytes (IC50 0.4-1.0 nM). Although the activities are superior to those of artemiside (IC50 1.5 nM) and artemisone (IC50 42.4 nM), the latter are more active against the liver stage Pb sporozoites (IC50 artemisone 28 nM). In addition, early results indicate these compounds tend not to display reduced susceptibility against parasites bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of artemisinin-resistant Pf. Thus, the advent of the amino-artemisinins including artemiside and artemisone will enable the development of new combination therapies that by virtue of the amino-artemisinin component itself will possess intrinsic transmission-blocking capabilities and may be effective against artemisinin resistant falciparum malaria.
Highlights
The introduction by the Chinese during the 1970s and 1980s of the antimalarial drug artemisinin 1 and its reduced derivative dihydroartemisinin (DHA) 2, the latter which was converted into the lactol ether artemether 3, and the hemiester artesunate 4 (Figure 1), ushered in a new era for the treatment of malaria (Brossi et al, 1988; Haynes, 2006)
We proposed use of the new artemisinin, which we term an oxidant drug by virtue of its ability to irreversibly oxidize reduced flavin cofactors, in combination with a redox drug such as a phenothiazine, e.g., methylene blue (MB), phenoxazine, naphthoquinone (Sidorov et al, 2016), quinone-imine, redox metal chelating agent (Parkinson et al, 2019), or other (Kubota and Gorton, 1999; Dharmaraja, 2017), with a third drug with a different mode of action (Coertzen et al, 2018)
Dose responses were assayed using a two-fold serial drug dilution on in vitro >95% ring stage intraerythrocytic P. falciparum parasites at 37◦C under 90% N2, 5% CO2, and 5% O2 atmospheric conditions, detecting both parasite lactate dehydrogenase activity as a metabolic marker following a 48 h drug exposure (1.5–2% parasitemia and 2% hematocrit; Makler et al, 1993) and SYBR Green I fluorescence as proliferative marker following a 96 h drug exposure (1% parasitemia and 1% hematocrit)
Summary
The introduction by the Chinese during the 1970s and 1980s of the antimalarial drug artemisinin 1 and its reduced derivative dihydroartemisinin (DHA) 2, the latter which was converted into the lactol ether artemether 3, and the hemiester artesunate 4 (Figure 1), ushered in a new era for the treatment of malaria (Brossi et al, 1988; Haynes, 2006). The introduction of the artemisinins was opportune, given that the hitherto most widely-used drug chloroquine (CQ) had become essentially ineffective due to the emergence in Cambodia in the 1960s and the rapid spread of the CQ-resistant strain of the principal parasite Plasmodium falciparum (Pf ) that causes malaria (Krogstad et al, 1987). In line with the WHO recommendation, the artemisinins were combined with longer half-life antimalarial drugs such as piperaquine, mefloquine, lumefantrine, or other, in artemisinin combination therapies (ACTs). These were subsequently used with considerable success in the treatment of malaria (Adjuik et al, 2002; Cui and Su, 2009; Eastman and Fidock, 2009; Wells et al, 2009; Angus, 2014). Increasing tolerance of the parasite to the longer half-life partner drugs in the ACT including piperaquine and mefloquine were recorded, eventually leading to overt treatment failures with ACTs (Duru et al, 2015; Leang et al, 2015; Spring et al, 2015; WHO, 2019)
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