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Malaria parasites are transmitted by mosquitoes and a substantial part of the parasite's complex life cycle takes place inside the insect. Parasite transmission starts with the uptake of parasite stages called gametocytes from the vertebrate host with the blood meal of a female vector mosquito, completing several weeks later with the injection of parasite stages called sporozoites into the vertebrate host by mosquito bite. The sporozoites form in their thousands inside ookinete-derived oocysts situated on the abluminal side of the mosquito midgut epithelium by a process of cell division known as sporogony. After their formation, sporozoites egress from the oocyst into the haemolymph, invade the salivary glands and mature to become infective to the vertebrate. This MicroCommentary reviews recent reports describing a conserved plasma membrane-associated protein of Plasmodium berghei, PBANKA_1422900, and its role in maintaining the shape and structural integrity of sporozoites in salivary glands and during inoculation into the vertebrate host. Combined results from three separate studies provide mechanistic insights into how this protein achieves structural maintenance of the sporozoite, and how in turn this promotes the sporozoite's ability to overcome several physical obstacles and allow it to establish infection in the vertebrate.

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Histone deacetylases (HDACs) have been identified as emerging antiplasmodial drug targets. In this work, we report on the synthesis, structure-activity relationships, metabolic stability and in vivo efficacy of new peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity. A mini library of HDAC inhibitors was synthesized using a one-pot, multi-component protocol or submonomer pathways. The screening of the target compounds for their activity against asexual blood stage parasites, human cell cytotoxicity, liver stage parasites, and selected human HDAC isoforms provided important structure-activity relationship data. The most promising HDAC inhibitor from this series, compound 3n, demonstrated potent activity against drug-sensitive and drug-resistant asexual stage P. falciparum parasites and was selective for the parasite versus human cells (Pf3D7 IC50 0.016 μM; SIHepG2/Pf3D7 573; PfDd2 IC50 0.002 μM; SIHepG2/PfDd2 4580) combined with activity against P. berghei exoerythrocytic liver stages (PbEEF IC50 0.48 μM). While compound 3n displayed high stability in human (Clint 5 μL/min/mg) and mouse (Clint 6 μL/min/mg) liver microsomes, only modest oral in vivo efficacy was observed in P. berghei infected mice. Together these data provide a foundation for future work to improve the properties of these dual-stage inhibitors as drug leads for malaria.

Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite- selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for the preparation of a panel of peptoid-based HDACi. Several compounds displayed potent activity against drug- sensitive and drug-resistant P. falciparum asexual blood stages, high parasite-selectivity and submicromolar activity against exo-erythrocytic forms of P. berghei. Our optimization study resulted in the discovery of the hit compound 1u which combines high activity against asexual blood stage parasites (Pf 3D7 IC(50): 4 nM; Pf Dd2 IC(50): 1 nM) and P. berghei exo-erythrocytic forms (Pb EEF IC(50): 25 nM) with promising parasite-specific activity (SI(Pf 3D7/HepG2): 2496, SI(Pf Dd2/HepG2): 9990, and SI(Pb EEF/HepG2): 400).

Novel malaria intervention strategies are of great importance due to the development of drug resistance in malaria endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by utilizing a one-pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure-activity as well as structure-toxicity relationships. Most compounds displayed potent activity against asexual blood stage P. falciparum parasites with IC(50) values ranging from 0.0052–0.25 µM and promising selectivity over mammalian cells (SI(Pf3D7/HepG2): 170–1483). In addition, several compounds showed encouraging submicromolar activity against P. berghei exo-erythrocytic forms (PbEEF). Our study led to the discovery of the hit compound (N-(2-(benzylamino)-2-oxoethyl)-N-(4-(hydroxycarbamoyl)benzyl)-4-i-propylbenzamide, 2h) as a potent and parasite-specific dual-stage antiplasmodial HDAC inhibitor (IC(50) (Pf3D7) = 0.0052 µM, IC(50) (PbEEF) = 0.016 µM).