Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Abstract

Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies

“…4 An aromatic side chain analogue of chloroquine, amodiaquine (2), however, retains activity against chloroquine-resistant Plasmodium strains. 5 Besides, it is an established fact that resistance against these 4-aminoquinolines is not a result of target modification but is caused by impaired accumulation of the drug at the target. 6,7 Consequently, amodiaquine is an attractive lead compound in the search for new antimalarials.…”

Primaquine Dosing Errors: The Human Cost of a Pharmaceutical Anachronism

“…1 It remains a cornerstone of the treatment of Plasmodium vivax and P. ovale, and as a gametocydal agent for P. falciparum. 2 In recent years, its indications have been expanded to include malaria prophylaxis, both primary and terminal, especially in areas where P. vivax is highly endemic.…”

Azide-alkyne cycloaddition en route to 1 H -1,2,3-triazole-tethered 7-chloroquinoline-isatin chimeras: Synthesis and antimalarial evaluation

“…The causative agent of the most lethal form of malaria, Plasmodium falciparum, has developed resistance to multiple drugs including chloroquine (CQ), previously the first line drug to treat malaria in most endemic countries [2]. CQ induces heme accumulation in the parasite digestive vacuole, leading to parasite death, possibly through degradation of parasite membranes [3].…”