Malaria remains one of the world’s most prevalent tropical diseases because of its high mortality and morbidity burden, as well as its economic and social impacts on the development of malaria-endemic countries. The emergence and spread of chloroquine-resistant Plasmodium falciparum, the causative agent of the most lethal form of human malaria, are major obstacles in the control of the disease. 1, 2 More recently, concern has been raised as to whether there is evidence of resistance to artemisinins, which could endanger the artemisinin combination therapies (ACTs) now widely adopted. Although continued attempts to develop a vaccine for malaria are ongoing, drugs continue to be the only treatment option,. 3, 4 The most currently used antimalarials are potent blood schizontocidals; ie, they act rapidly against the parasite forms that invade erythrocytes and cause the well-described malaria symptoms. 2 However, before the onset of clinical symptoms, the clinically silent pre-erythrocytic life cycle stages, transmitted by Anopheles mosquitoes, invade and develop in the liver (Figure 1). The sporogonic stage develops within a parasite oocyst in the mosquito midgut from which sporozoites are released and invade the salivary glands. Sporozoites deposited in the mammalian host’s circulation during the mosquito’s blood meal reach the liver and infect hepatocytes. Plasmodium liver stages (LS) grow and undergo nuclear replication within a parasitophorous vacuole, culminating in the release of tens of thousands of merozoites into the bloodstream. This intrahepatic developmental process takes approximately 2 days in the case of rodent Plasmodium parasites and 7− 14 days for human Plasmodium spp., depending on parasite species. 5 Free merozoites rapidly adhere to and invade erythrocytes, replicate, and generate further infectious merozoites. Blood parasitemia then develops, leading to clinical symptoms. 6, 7 The LS of Plasmodium spp. obligatorily precedes blood stages and therefore represents a potential drug target. 5, 8 Full inhibition of LS parasite development would lead to true causal prophylaxis. 1 Transmission would also be interrupted because it depends on gametocytes that mature in red blood cells, following completion of the liver stage of infection. Furthermore, the low number of hepatic forms substantially reduces the likelihood of emergence of drug-resistant parasites. 8 The difficulties in developing a drug with true causal prophylactic activity against malaria are mostly related to the biology of Plasmodium spp. LS and the inherent technical difficulties in studying them. 9 Recently, a proteome and transcriptome analysis revealed a set of proteins specific to the LS of malaria, including those of the highly active type II fatty acid synthesis (FAS-II) pathway. The redox metabolism, tricarboxylic acid cycle, electron transport system, and protein metabolism account for other overrepresented pathways. 10 Also, infectiousness of sporozoites is variable among batches and in vivo studies are often carried out in mice models infected with P. berghei or P. yoelii. 8 This represents a major limitation, since the rodent malaria parasites do not form latent liver forms (hypnozoites) which are present in P. vivax and P. ovale and can cause relapses of malaria long after initial bloodstream infections have been cleared. Most of the known LS inhibitors have resulted from traditional medicinal chemistry programs, which started over 70 years ago. However, those studies mostly explored 8-aminoquinolines, and thus, there is a relative lack of chemical diversity among potent inhibitors. More recently, efforts toward finding novel leads have also been supported by …