The outlook for new antimalarials is now better than it has been for decades, thanks to public–private
partnerships and increased funds for countries to buy drugs. Despite renewed international commitment to
research and control, the reality for many patients is as inadequate as it was in the past. There were an estimated
225 million episodes of malaria in 2009 with eighty-six percent located in the African Region. About
~ 881 000 malaria deaths in 2006, of which 85% were of children under 5 years of age. Africa had more
funds for malaria control than any other, and reported a larger increase in funding than any other region.
Constituting 10% of the overall disease burden, malaria places a substantial strain on health services and
costs Africa about $12 billion in lost production each year. Furthermore, malaria consumes around one
fourth of household incomes in most African endemic countries, reducing access to preventive interventions
and lifesaving services. Annual funding for malaria control has increased at least 10-fold during the
last 15 years, now approximating $ 600-800 million annually. Three major tools are currently used to combat malaria: controlling
mosquitoes, reducing human–vector contact, and preventing and treating disease with drugs. Research must focus on tools
that are suited to constraints in the field. The cornerstone of malaria control worldwide remains effective with the use of inexpensive
drugs. But resistance of the Plasmodium parasite to the most popular drug in Africa, chloroquine, is now widespread
and few alternatives have been licensed over the past 20 years. Artemisinin derivatives offer great hope for reducing malaria
morbidity and transmission. They are effective in combination with other antimalarials (artemisinin-based combined therapies
or ACTs), which should also delay the development of resistance and ACTs have now been adopted globally as the first line of
treatment. But delayed rates of parasite clearance after ACTs treatment in the Thai - Cambodian border were recently reported.
Irrational use of artemisinin monotherapies is undermining ACTs. It cannot be also excluded that resistance could wipe out
artemisinin combination in an unpredictable future. With few new drugs in late-stage development, resistance to ACTs could
render ineffective many of the endoperoxide drug candidates being developed as synthetic alternatives to artemisinin. ACTs are
now the first line treatment for imported malaria in non-endemic countries. It could be speculated that endemic area resistance
will have a direct impact on treatment failure risk for non-endemic patients. Global warming could bridge the endemic and nonendemic
fears caused by malaria resistance. The search for novel drug candidates to overcome the resistance of the current antimalarial
drugs has been an active area of research for the past 20 years. Up to the end of 1990’s, antimalarial drug development
has been severely limited by a lack of interest of pharmaceutical companies in investing large sums for the development
of drugs for a disease of disadvantaged populations. It is remarkable that almost all of the first generation antimalarials have
been developed through government research programs [chloroquine (CQ), primaquine (PQ), mefloquine (MQ)], the fortuitous
identification of efficacy in natural products (quinine, artemisinin), or the identification of antimalarial potency in drugs marketed
for other indications (folate antagonists, sulfas, antibiotics, atovaquone). The strategy of Medicines for Malaria Venture
(MMV) financing collaborations that combine drug discovery expertise of industry and academia and the malaria expertise of
academic groups appears now to be the most successful way to produce clinical candidates, in addition to consortiums funded
by the European Union, organizations such as the Bill and Melinda Gates Foundation, Wellcome-Trust Fund, the National Institutes
of Health, and other European government funding agencies.
One critical point when starting a research project aimed at the development of new antimalarial drugs with a cheap and
efficient synthesis is where to start: do we use known pharmacophores (with established mechanism of action and known targets)
as the starting point with the goal to provide new analogues with better and safer pharmacological profile and offer new
hope to combat for drug resistance, or do we depend on the outcome on high-throughput phenotypic screenings for the identification
of hits with a new mechanism of action?
The focus of this special issue is on new approaches and mechanisms, but also on approaches that provide new candidates
embedded with remarkable biological profile that are synthetic analogues of known pharmacophores. Such issue present review
papers where significant medicinal chemistry efforts have placed hope for the identification of new therapies to combat this
Picot et al. comments on facts and thoughts on the development of antimalarial drugs, from medicinal chemists, biologists
and clinicians. Their review also provide some important clinical and economic impacts and demands and raise different questions
about the “attitude” of academia and industry to respond to the demand of new antimalarial drug candidates based on
well-established and overused concepts and dogmas. Nepveu et al. outlines progress towards the identification of indolone Noxides
as new redox-pharmacophores and review their latest developments with the identification of potent pre-clinical candidates.
Peyrottes et al. reviews their recent efforts on exploring prodrug approaches for Albitiazolium and its analogues in order
to obtain affordable and orally available drugs for uncomplicated malaria treatment. André-Barrès et al. reviews their work on
the development of structural analogues of bicyclic peroxides belonging to the G factors family presenting antimalarial properties,
including bicyclic peroxides both with various hybrid molecules containing the endoperoxide framework. Elucidation of
their mechanism of action and identification of intermediates are also presented. Biot et al. reports on the development of Ferroquine
a mid-stage clinical candidate and discuss about its development, different ideas about its specific mechanism of action
and comments on the fact that despite structural analogy to chloroquine, ferroquine has a distinct mechanism of action. An ultimate theory reconciling the hydrogen bond and the redox mechanisms hypotheses of ferroquine and fitting a wider range of
published experimental results are presented. Manetsch et al. reviews their research efforts in the development of 4(1H)-
Pyridone and 4(1H)-Quinolone derivatives, as antimalarials with erythrocytic, exoerythrocytic, and transmission blocking activities.
Structure-activity relationship and structure-property relationship studies, biological evaluation in vitro and in vivo, as
well as pharmacokinetics of these chemotypes are discussed. Despite that these structures are known for over 20-30 years, different
research groups including Manetsch revisited the development of these chemotypes as antimalarials targeting multiple
stages of the parasites, and the new structures have potential to be unique antimalarials with blood stage activity, exoerythrocytic
stage activity and transmission blocking activity. Rawat et al. review the recent studies towards the development of 4-
aminoquinoline based molecular hybrids as antimalarials. The concept of generating hybrid molecules by pharmacophoric hybridization
approach is a very popular methodology and represents an alternative to other existing strategies of drug development.
It is likely that the future antimalarial drug discovery pipeline will include a mixture of successful identification of clinical
candidates from both target and phenotypic approaches, but also structural manipulation based on well-established skeletons.
The success of such approaches will be dependent on constant research funding, shared resources and shared knowledge. The
time and effort of the authors contributing to this special issue is gratefully acknowledged.