Current Topics in Medicinal Chemistry - Volume 12, Issue 5, 2012

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.

The present review describes the development of synthetic cyclic peroxides, which are designed to surpass the antimalarial activity of the lead molecule, the natural product (+)-artemisinin and some of its C10 derivatives. To begin with, tricyclic and bicyclic 1,2,4-trioxanes are taken to show how the pharmacophore was identified and chirality proved to be irrelevant. The action of ferrous salts on trioxanes illustrates the structural elements that are needed so that reductive breaking of the peroxide bond leads to C-centered radicals, the alleged parasiticidal agents. Views are expressed on how heme, Plasmodium SERCA, and plain ferrous ions, either as targets or activators, could be implicated in the mode of action. Thereafter, news about 1,2,4-trioxolanes, 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, 1,2-dioxolanes, and 1,2-dioxanes is recounted, emphasizing aspects of design, mechanism, and the importance of the adamantane entity for buttressing activity. News about compounds made up of a trioxane covalently bound to aminoquinoline, so-called hybrid molecules, is reported together with a view that they might be better than mechanical mixtures. No new antimalarial can be considered without a word about the risk posed by the parasite developing resistance. The review is not intended to be exhaustive. Some gaps prior to 2009 are filled in, while the later literature up to the end of July 2011 has been covered. Artemisinin and its derivatives fall outside the scope of the review. Nevertheless, some mechanistic insights garnered from artemisinin, which are relevant to synthetic peroxides, are included.

This short review tells the story of how Reversed Chloroquine drugs (RCQs) were developed. These are hybrid molecules, made by combining the quinoline nucleus from chloroquine (CQ) with moieties which are designed to inhibit efflux via known transporters in the membrane of the digestive vacuole of the malaria parasite. The resulting RCQ drugs can have potencies exceeding that of CQ, while at the same time having physical chemical characteristics that may make them favorable as partner drugs in combination therapies. The need for such novel antimalarial drugs will continue for the foreseeable future.

Falcipains are Plasmodium falciparum cysteine proteases involved in different processes of the erythrocytic cycle of the malaria parasite like hydrolysis of host hemoglobin, erythrocyte invasion, and erythrocyte rupture. These proteases constitute promising targets in the search for novel therapies that would ease the burden caused by the increasing resistance to current antimalarial drugs. Despite biochemical characterization of four falcipains so far, the search for new falcipain inhibitors has been limited to falcipain-2 and/ or falcipain-3, due to their interesting hemoglobinase capacity and the ample availability of tools to study them. We describe progress towards the discovery of promising falcipain inhibitors, in the light of their drug-like properties and the effect of the inhibition of several of these cysteine proteases. Some important aspects to focus on future development of falcipain inhibition are also discussed.

Plasmepsins are the aspartic proteases of Plasmodium that play key roles in the survival of the parasite in its host. The plasmepsins of the digestive vacuole play an important role in hemoglobin degradation, providing the parasite with a vital source of nutrients. Recently, plasmepsin V has been shown to be an essential protease, processing hundreds of parasite proteins for export into the host erythrocyte. The functions of the remaining plasmepsins have yet to be discovered. Over the past decade, much effort has been placed towards developing plasmepsin inhibitors as antimalarial agents, particularly targeting the digestive vacuole. This review will highlight some of the recent work in this field with a particular focus on target druggability and strategies for identifying plasmepsins inhibitors as effective antimalarial drugs. Given recent advances in understanding the fundamental roles of the various plasmepsins, it is likely that the most effective antimalarial plasmepsin targets will be the non-digestive vacuole plasmepsins.

Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance.

Antimalarial drug discovery has historically benefited from the whole-cell (phenotypic) screening approach to identify lead molecules in the search for new drugs. However over the past two decades there has been a shift in the pharmaceutical industry to move away from whole-cell screening to target-based approaches. As part of a Wellcome Trust and Medicines for Malaria Venture (MMV) funded consortium to discover new blood-stage antimalarials, we used both approaches to identify new antimalarial chemotypes, two of which have progressed beyond the lead optimization phase and display excellent in vivo efficacy in mice. These two advanced series were identified through a cell-based optimization devoid of target information and in this review we summarize the advantages of this approach versus a target-based optimization. Although the each lead optimization required slightly different medicinal chemistry strategies, we observed some common issues across the different the scaffolds which could be applied to other cell based lead optimization programs.