Malaria continues to be a life-threatening disease, causing roughly 241 million cases and an estimated 627,000 deaths in 2020, mostly among African children, although in 2020 nearly half of the world’s population was at risk of malaria. There is a big financial burden for antimalarial treatment; direct costs (for example, illness, treatment, premature death) have been estimated to be at least US $12 billion per year and the cost in lost economic growth is many times more than that. Human malaria is caused by five parasites, including Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. Plasmodium falciparum (p. falciparum) is the most virulent species, which is responsible for the majority of human malaria-related morbidity and mortality. The transmission of malaria starts with injection of sporozoites, during the bite of a female Anopheles mosquito. The sporozoites then travel to liver cells and begin asexual merozoites production. Through infecting new red blood cells, the merozoites either initiate asexual multiplication cycles or develop into sexual gametocytes. Gametocytes are taken up by a fertilized mosquito when biting an infected person, where the male and female gametocytes fuse, form a zygote, and develop to new sporozoites for human infections. Although current therapies can clear the asexual stages of malaria parasites, their abilities to eliminate the gametocyte and liver stages are limited. Primaquine (PQ) is the only drug that can kill both gametocytes and liver stages. Promising malaria eradication has been recently reported using a PQ and artemisinin combination therapy (ACT) in test regions. However, the PQ is not widely recommended for treating malaria due to causing hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. Thus, new anti-gametocyte drugs are urgently needed.

Previously, we have shown that mTOR inhibitor Torin2 has potent gametocytocidal activity. Through chemistry optimization, we have developed a series Torin2 analogues capable of selectively killing parasites. We have also shown that imidazo [1,5]quinoline analogues can selectively killing asexual and sexual parasites. Through chemistry optimization, we have identified 2-imino Torin analogues and 2-iminoimidazo[1,5]quinoline analogues that are efficacious in killing asexual, gametocyte, and liver stage parasites. These 2-imino analogues have demonstrated single oral dose cure in multiple in vivo efficacy studies in mice.