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Current Topics in Medicinal Chemistry
ISSN (Print): 1568-0266
ISSN (Online): 1873-5294
VOLUME: 14
ISSUE: 14
DOI: 10.2174/1568026614666140808152357









Editorial (Thematic Issue: The Medicinal Chemistry and Drug Development of Novel Antimalarials)

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Author(s): Maurice Medebielle
Pages 1635-1636 (2)
Abstract:
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 disease. 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.
Affiliation:
Universite Claude Bernard Lyon 1 ICBM UMR CNRS-UCBL 5246, Equipe SMITH 43 bd du 11 Novembre 1918, 69622 Villeurbanne Cedex France.