Table 5.

Novel antimalarials in development [102, 105, 106].

Drug class	Drug names	Mechanism of action	Notes
Malaria parasite protease inhibitors	(i) Cysteine and serine protease inhibitor (leupeptin) (ii) Cysteine protease inhibitor (E-64, epoxomicin, lactacystin, MG132, WEHI-842, WEHI-916, chymostatin) (iii) Aspartic protease inhibitor (pepstatin) (iv) Serine protease inhibitor (LK3)	Drugs in this class disrupt malarial proteases, which inhibit haemoglobin degradation by intraerythrocytic trophozoites and the parasite development in the erythrocyte stages	A cysteine protease inhibitor (E-64) and an aspartic protease inhibitor (pepstatin) previously demonstrated synergistic inhibition towards P. falciparum development. In addition, E-64 blocked globin hydrolysis. Previous studies have indicated that several cysteine protease inhibitors inhibited both P. falciparum growth and haemoglobin degradation
Phosphatidylinositol 4-kinase (PfPI4K) inhibitor	(i) UCT943 (ii) Imidazopyrazines (KAF156) (iii) Aminopyridine (iv) Compound 1294	Inhibition of phosphoinositide lipid kinases (PIKs) inhibits the activation of lipids by preventing lipid phosphorylation and subsequently inhibits proliferation, survival, trafficking, and intracellular signalling	PI(4)K inhibitors block the intracellular development of multiple Plasmodium species at each stage of infection in the host KAF156 is currently in phase II clinical trials Compound 1294 previously inhibited the transmission of parasites from mosquitoes to humans
Transporter inhibitors	(i) Anion transporter inhibitors (phlorizin, dantrolene, furosemide, and niflumate) (ii) Inhibitors of choline influx into parasite-infected erythrocytes (glibenclamide, meglitinide, and tolbutamide)	Transporter inhibitors inhibit transporters, such as the plasmodial surface anion channel (PSAC) and the parasitophorous vacuolar membrane (PVM), which are essential for the entrance of metabolites, electrolytes, and nutrients into the parasite	Of these transporters, PSAC is the most promising target due to its critical role in several types of nutrient acquisition into the intracellular parasite as well as in maintaining a low Na+ and K+ permeability ratio in parasites
Plasmodium sugar transporter inhibitor	(i) Long-chain O‐3‐hexose derivative (compound 3361)	Inhibits the uptake of glucose by P. Falciparum hexose transporter (PFHT), as P. falciparum depends on glycolysis (the uptake of glucose) for replication	Compound 3361 previously inhibited the uptake of glucose and fructose by PFHT in P. vivax, induced death in P. falciparum, and reduced multiplication of P. berghei in a mouse model
Parasite's lactate transporter inhibitor	(i) MMV007839 (ii) MMV000972	Inhibition of the lactate H+ symport transport system inhibits lactate export and glucose uptake in the parasite	Compounds, such as MMV007839 and MMV000972, previously induced death in P. falciparum
P-type Na+ ATPase inhibitor (PfATP4)	(i) Cipargamin (ii) (+)-SJ733 (iii) KAE609	Inhibition of P-type ATPase transporter (PfATP4) inhibits the parasite's primary Na+-efflux pump, leading to increased cytoplasmic Na+ levels and subsequent death	KAE609 and cipargamin are currently in phase II clinical trials and were previously shown to display accelerated parasite clearance compared to artemisinins
V-type H+-ATPase inhibitor	(i) MMV253	V-type H+-ATPase inhibitors inhibit H+ efflux in parasites	MMV253 previously inhibited the V-type H+ ATPase through mutant selection and whole-genome sequencing
Aquaporin-3 inhibitor	(i) Auphen	Aquaporin-3 inhibitors inhibit the entry of glycerol into P. berghei and contributes to the replication of the parasite during the asexual intraerythrocytic stages	Aquaporin-3 inhibitor, Auphen, previously inhibited P. berghei in hepatocytes and P. falciparum in erythrocytes
Choline transport inhibitor	(i) Albitiazolium (ii) G25 (iii) T3	Choline transport inhibitors inhibit choline influx into the parasite, which is essential for the production of phosphatidylcholine (an important component of parasite cell membranes)	Albitiazolium is currently in phase II clinical trials G25 previously exhibited potent and highly selective cytotoxicity against P. falciparum and P. vivax in vitro
Dihydroorotate dehydrogenase inhibitor	(i) DSM190 (ii) DSM265 (iii) P218	Dihydroorotate dehydrogenase inhibitors inhibit de novo pyrimidine synthesis in parasites, leading to death	DSM265 is currently in phase II clinical trials
Isoprenoid biosynthesis inhibitor	(i) Fosmidomycin (ii) MMV019313 (iii) MMV008138	Isoprenoid biosynthesis inhibitors inhibit 1-deoxy-D-xylulose-5-phosphate (DOXP) reductoisomerase in pathways specific to P. falciparum for asexual replication	MMV019313 previously displayed selective cytotoxicity towards parasites
P. falciparum translational elongation factor 2 inhibitor	(i) Sordarin (ii) M5717	P. falciparum elongation factor 2 inhibitors inhibit a ribosome component responsible for catalysing the GTP-dependent translocation of the ribosome along messenger RNA and thus inhibit protein synthesis in eukaryotes	M5717 is currently in phase I clinical trials