Malaria, a devastating infectious disease caused by Plasmodium spp., leads to roughly 655,000 deaths per year, mostly of African children. To compound the problem, drug resistance has emerged to all classical antimalarials and may be emerging for artemisinin-based combination therapies. To address the need for new antimalarials with novel mechanisms, several groups carried out phenotypic screening campaigns to identify compounds inhibiting growth of the blood stages of Plasmodium falciparum. In this review, we describe the characterization of these compounds, explore currently ongoing strategies to develop lead molecules, and endorse the concept of a “malaria box” of publicly accessible active compounds.
Malaria is a mosquito-borne disease that kills roughly 655,000 people every year, mostly young children in Africa. Malaria affects roughly 215 million patients annually (World Health Organization, 2011), and approximately one third of the world’s population is at risk for contracting the disease. The World Health Organization has announced a new campaign for global malaria eradication (Wells et al., 2009).
Mosquito-borne diseases are usually controlled by a combination of vector control, vaccines, and chemotherapy. In the case of malaria, economical vector control strategies, including insecticide-impregnated bed nets and localized spraying, have been deployed with success (Okumu and Moore, 2011). Additionally, progress is being made toward effective vaccines with the RTSS vaccine from GlaxoSmithKline (GSK), giving some protection (Schwenk and Richie, 2011). Nonetheless, chemotherapy remains the dominant component of malaria control. Unfortunately, clinical resistance has emerged for most available drugs (Petersen et al., 2011), and there are recent indications of the emergence of resistance to the artemisinin components of artemisinin-based combination therapies, which are a cornerstone of current antimalarial treatment strategies (Dondorp et al., 2009, Mok et al., 2011, Saralamba et al., 2011 and Veiga et al., 2011).
Therefore, new antimalarials are urgently needed. The focus of the discovery process is on new medicines that are structurally distinct from existing drugs, act by novel mechanisms, and avoid being acted upon by drug transporters overexpressed or overactive in multi-drug-resistant malaria. In the late 2000s, three groups, one in academia (St. Jude Children’s Research Hospital) (Guiguemde et al., 2010) and two in industry (GSK [Gamo et al., 2010] and Novartis [Plouffe et al., 2008]), identified novel leads using screening campaigns measuring the growth inhibitory potential of compounds acting on Plasmodium falciparum co-cultured during its asexual stages in human erythrocytes.
In this review, we discuss the driving force for conducting these screens; the results, including similarities and differences between the compounds identified; and the need for further innovation and work in understanding the underlying cellular and physiologic mechanisms by which the new classes of antimalarials work.
Volume 19, Issue 1, 27 January 2012, Pages 116–129
High-Priority Series from Each Group
Molecule Series Example Institution Development Stage Dihydropyridine SJ000025081 SJCRH Lead optimization Diaminonaphthoqinone SJ000030570 SJCRH Lead optimization Dihydroisoquinoline SJ000101247 SJCRH Preclinical Carboxamide GSK2611622A GSK Lead optimization Indoline TCMDC-139046 GSK Lead optimization Alkylpyrazole TCMDC-134142 GSK Lead optimization Thienopyrazole TCMDC-123580 GSK Lead optimization Aminopiperidine TCMDC-124833 GSK Lead optimization Spiroindolone NITD609 Novartis Phase I Imidazolo piperazine Novartis Preclinical Benzamide Novartis Lead optimization Pyrimidine-4,6-diamine Novartis Lead optimization
- In retrospective analysis, it is clear that each group independently detected most of the chemotypes present in this table, but, although uncoordinated, each group focused later efforts on a restricted set of series identified from their screens
Chemical structures of anti–malarials
Anthony et al. Malaria Journal 2012 11:316 doi:10.1186/1475-2875-11-316