Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

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 (IC 50 0.4-1.0 nM). Although the activities are superior to those of artemiside (IC 50 1.5 nM) and artemisone (IC 50 42.4 nM), the latter are more active against the liver stage Pb sporozoites (IC 50 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 Wong et al. Transmission-Blocking Amino-Artemisinins for New ACTs 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.

Anti-Melanoma Activities of Artemisone and Prenylated Amino-Artemisinins in Combination With Known Anticancer Drugs

“…The second-generation derivative artemisone 4, prepared from dihydroartemisinin (DHA) 3, itself a derivative of artemisinin ( Haynes et al, 2006 ; Chan et al, 2018 ) and the novel prenylated piperazine derivatives 6 and 7 prepared by direct alkylation by the prenyl bromide of the amino-artemisinin 5 bearing a piperazine group at C-10 ( Figure 2 ) are included in this investigation. The compound 5 is readily obtained in one scalable step from DHA and piperazine ( Wu et al, 2018 ; Wong et al, 2020 ). Of particular relevance to this work, it is noted that DHA 3 itself induces apoptosis in cultured human metastatic melanoma cells (A375, LOX and G361), with phosphatidylserine (PS) externalization, activation of procaspase 3 and increased generation of intracellular ROS ( Cabello et al, 2012 )…”

Malaria: Introductory Concepts, Resistance Issues and Current Medicines

“…In addition, these compounds tend not to display reduced susceptibility against Plasmodium species bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of artemisinin-resistant falciparum malaria. Thus, the advent of the amino-artemisinins will enable the development of novel combination drugs that by virtue of the amino-artemisinin component itself will possess intrinsic transmission-blocking abilities and may be effective against artemisinin-resistant falciparum malaria [106,107]. Agents in red are still in development [100].…”

First principle study of silver nanoparticle interactions with antimalarial drugs extracted from Artemisia annua plant

“…Amongst them, the Artemisia annua consisting of a group of plants known as wormwoods have been used for some medicinal purposes, including malaria, for centuries (Dalrymple 2013). Artemisinin, which is an important bioactive component found in Artemisia annua leaves and flowers, is extracted from this plant and is the basis for the WHO-recommended anti-malaria combination therapies used in millions of adults and children each year with few, if any, side effects (Wong et al 2020). Artesunate and Artemether are the two most significant Artemisinin derivatives and promising novel drugs to treat pulmonary fibrosis by inhibiting pro-fibrotic molecules associated with pulmonary fibrosis (Wang et al 2015;Suputtamongkol et al 2001).…”