Editorial [Hot Topic :The Medicinal Chemistry of Novel Approaches for the Treatment of Malaria (Guest Editor: Marvin J. Meyers)]

For centuries, the human race has been fighting the devastating effects of malaria, caused by the parasite Plasmodium. In 2009, there were 225 million cases of malaria resulting in 781,000 deaths according to the World Health Organization (WHO) [1]. Significant strides towards eradication were made during the early to mid-1900s through the introduction of fast-acting antimalarial agents such as chloroquine (CQ), sulphadoxine-pyrimethamine and other antimalarial drugs. The rise of resistance to chloroquine and other antimalarial drugs has led to a resurgence of the disease in the developing world during the latter half of the 20th century. Especially hard hit is Africa where the majority of malaria-related deaths occur due to P. falciparum, the most lethal to man of the Plasmodium species. The introduction of artemisinin and artemisinin combination therapies (ACTs) in 2005 has begun to reverse the trend. While this is a good sign, there have been reports of resistance to artemisinin in Southeast Asia [2]. As the artemisinins are the only fully effective class of antimalarial drugs available today, it is crucial that additional antimalarial drugs be developed with novel mechanisms of action as the next line of defense to combat developing resistance to known drugs. These efforts, along with efforts to control the transmission of malaria by the mosquito, such as insecticidetreated bed nets, will be needed if successful global eradication of malaria is to be achieved in the first half of this century. The past ten to fifteen years has seen a renewed investment of time, talent and resources towards the development of new antimalarial therapies [3]. Organizations such as the Bill and Melinda Gates Foundation, Wellcome-Trust Fund and the National Institutes of Health have provided funding. Medicines for Malaria Venture (MMV) is providing a conduit for antimalarial drug discovery and advancement of novel antimalarials into the clinic. As a result, a global antimalarial drug discovery pipeline has been established with late stage projects aimed at improving properties of current antimalarial drugs (e.g., increasing the half-life of artemisinin) and mid- to early-stage projects for new drugs for clinically validated targets to overcome resistance of current antimalarials. This early stage pipeline also includes clinical candidates and preclinical drug discovery efforts for new mechanisms and approaches, which complement the current mid- to late-stage efforts by providing compounds to combat drug resistance. The focus of this special issue is on these new approaches and mechanisms, where significant medicinal chemistry efforts have placed hope for the identification of new therapies to combat this disease. Arguably, one of the most advanced new areas of antimalarial drug discovery is the synthetic peroxide class. Jefford reviews the recent progress of this field, which includes compounds that have advanced into clinical trials. In an effort to rescue well-established antimalarial drugs, Peyton outlines progress towards combating the mechanism of CQ resistance using “reversed-CQ” agents, which are hybrids of CQ and resistance reversal agents, primarily inhibitors of the chloroquine-resitance transporter. Target-based drug discovery represents an important portion of antimalarial research. For example, inhibition of the Plasmodium dihydrooratate dehydrogenase (DHODH) provides a promising novel mechanism of action, but awaits clinical validation and has been recently reviewed elsewhere [4]. Over the past 10 years or so, significant efforts have been focused on inhibition of hemoglobin degradation pathways, an important food source for the parasite. Marco and Coteron review progress on inhibition of the cysteine protease falcipain family. In an examination of the evidence for targeting inhibition of the aspartic protease plasmepsin family, Meyers and Goldberg review the shift in focus from inhibition of the redundant digestive vacuole plasmepsins to recent discoveries of other plasmepsins with essential roles in the parasite (e.g., plasmepsin V). Zhang, et al., review the developing field of malarial kinases as novel targets for therapeutic intervention. While target-based drug discovery has yielded some attractive antimalarial inhibitors, most antimalarial drugs have been identified as the result of phenotypic screens. Recently, scientists at GSK, Novartis, and St. Jude's have all reported on large scale high-throughput phenotypic screening efforts revealing thousands of new antimalarial hits, shared with the broader antimalarial research community, as potential starting points for drug discovery [5-8]. Chatterjee and Yeung provide perspective and experiences in the development of such hits into clinical candidates. 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. The success of such approaches will be dependent on high quality science, shared resources and shared knowledge. The time and effort of the authors contributing to this special issue is gratefully acknowledged.