Medical quinolines Malaria Hemozoin formation in P. falciparum: many antimalarials are strong inhibitors of hemozoin crystal growth. The lysosomotropism character of<unk>  is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropism properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases, autophagy, and apoptosis. Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade haemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell. Haemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite bio crystallizesheme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.<unk>  enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole.<unk>  then becomes protonated (to<unk> 2+), as the digestive vacuole is known to be acidic (pH 4.7);<unk>  then cannot leave by diffusion.<unk>  caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme build-up.<unk>  binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. Parasites that do not form hemozoin are therefore resistant to<unk> . Resistance in malaria Since the first documentation of P. falciparum<unk>  resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of<unk>  against P. falciparum has declined as resistant strains of the parasite evolved. Resistant parasites are able to rapidly remove<unk>  from the digestive vacuole using a transmembrane pump.<unk> -resistant parasites pump<unk>  out at 40 times the rate of<unk> -sensitive parasites; the pump is coded by the P. falciparum<unk>  resistance transporter (PfCRT) gene. The natural function of the<unk>  pump is to transport peptides: mutations to the pump that allow it to pump<unk>  out impairs its function as a peptide pump and comes at a cost to the parasite, making it less fit. Resistant parasites also frequently have mutation in the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to PfCRT. An altered<unk> -transporter protein, CG2 has been associated with<unk>  resistance, but other mechanisms of resistance also appear to be involved. Verapamil, a Ca2+ channel blocker, has been found to restore both the<unk>  concentration ability and sensitivity to this drug. Other agents which have been shown to reverse<unk>  resistance in malaria are<unk> orpheniramine, gefitinib, imatinib, tariquidar and zosuquidar.<unk>  is still effective against poultry malaria in Thailand. Sohsuebngarm et al 2014 test P. gallinaceum at Chulalongkorn University and find the parasite is not resistant. Sertraline, fluoxetine and paroxetine reverse<unk>  resistance, making resistant biotypes susceptible if used in a cotreatment. Antiviral<unk>  has antiviral effects against some viruses. It increases late endosomal and lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release of the virus requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.<unk>  also seems to act as a zinc ionophore that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase. Other<unk>  inhibits thiamine uptake. It acts specifically on the transporter SLC19A3. Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.
Chloroquine
Primaquine
Amodiaquine
Artemether
Tafenoquine
Piperaquine
Ajmalicine
Mefloquine