The global research community must take up the challenge to work toward the eradication of malaria. In the past, malaria research has focused on drugs and vaccines that target the blood stage of ...infection, and mainly on the most deadly species, Plasmodium falciparum, all of which is justified by the need to prevent and treat the disease. This work remains critically important today. However, an increased research focus is now being placed on potential interventions that aim to kill the parasite stages transmitted to and by the mosquito vector because they may represent more vulnerable targets to stop the spread of malaria. Here, we highlight some of the research into malaria parasite biology that has the potential to provide new intervention targets for antimalarial drugs and vaccines.
Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a ...focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of “microwave flash heating” in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.
Out of the kitchen into the laboratory: Direct heating by microwave irradiation (see picture) in many cases enables synthesis to be carried out in a fraction of the time required with conventional heating techniques. The use of microwave heating in organic synthesis is growing rapidly and the advantages not only include faster reaction times, but also higher product yields, cleaner reactions, better controllability, and reproducibility.
A mild, catalyst‐free electrochemical oxytrifluoromethylation of alkenes has been developed. The procedure is based on the paired electrolysis of sodium triflinate and water in an undivided cell. ...Anodic oxidation of the triflinate anion generates trifluoromethyl radicals that react with the alkene. Water plays a dual role as oxidant for the cathode and nucleophile. The method has been utilized to prepare a diverse set of 1‐hydroxy‐2‐trifluoromethyl compounds in moderate to excellent yields (27–94 %). Alcohols have also been tested as nucleophiles for this versatile method with moderate yields. Facile recycling of the electrolyte has been demonstrated, and application of electricity avoids the use of stoichiometric amounts of oxidizers in a safe and environmentally benign reaction.
Electricity and water are key ingredients in this alkene difunctionalization method. Paired electrolysis of sodium trifluoromethanesulfinate and water in an undivided cell enables a mild, catalyst‐free oxytrifluoromethylation of styrenes. Trapping experiments provide evidence of a mechanism involving three radical intermediates.
Tailored to the needs of medicinal and natural products chemists, the second edition of this unique handbook brings the contents up to speed, almost doubling the amount of chemical information with ...an additional volume. As in the predecessor, a short introductory section covers the theoretical background and evaluates currently available instrumentation and equipment. The main part of the book then goes on to systematically survey the complete range of published microwave-assisted synthesis methods from their beginnings in the 1990s to mid-2011, drawing on data from more than 5,000 reports and publications. Throughout, the focus is on those reactions, reagents and reaction conditions that work, and that are the most relevant for medicinal and natural products chemistry. A much expanded section is devoted to combinatorial, high-throughput and flow chemistry methods.
Determining the genetic basis of fitness is central to understanding evolution and transmission of microbial pathogens. In human malaria parasites (Plasmodium falciparum), most experimental work on ...fitness has focused on asexual blood stage parasites, because this stage can be easily cultured, although the transmission of malaria requires both female Anopheles mosquitoes and vertebrate hosts. We explore a powerful approach to identify the genetic determinants of parasite fitness across both invertebrate and vertebrate life-cycle stages of P. falciparum. This combines experimental genetic crosses using humanized mice, with selective whole genome amplification and pooled sequencing to determine genome-wide allele frequencies and identify genomic regions under selection across multiple lifecycle stages. We applied this approach to genetic crosses between artemisinin resistant (ART-R, kelch13-C580Y) and ART-sensitive (ART-S, kelch13-WT) parasites, recently isolated from Southeast Asian patients. Two striking results emerge: we observed (i) a strong genome-wide skew (>80%) towards alleles from the ART-R parent in the mosquito stage, that dropped to ~50% in the blood stage as selfed ART-R parasites were selected against; and (ii) repeatable allele specific skews in blood stage parasites with particularly strong selection (selection coefficient (s) ≤ 0.18/asexual cycle) against alleles from the ART-R parent at loci on chromosome 12 containing MRP2 and chromosome 14 containing ARPS10. This approach robustly identifies selected loci and has strong potential for identifying parasite genes that interact with the mosquito vector or compensatory loci involved in drug resistance.
Plasmodium falciparum and Plasmodium vivax cause the majority of human malaria cases. Research efforts predominantly focus on P. falciparum because of the clinical severity of infection and ...associated mortality rates. However, P. vivax malaria affects more people in a wider global range. Furthermore, unlike P. falciparum, P. vivax can persist in the liver as dormant hypnozoites that can be activated weeks to years after primary infection, causing relapse of symptomatic blood stages. This feature makes P. vivax unique and difficult to eliminate with the standard tools of vector control and treatment of symptomatic blood stage infection with antimalarial drugs. Infection by Plasmodium is initiated by the mosquito-transmitted sporozoite stage, a highly motile invasive cell that targets hepatocytes in the liver. The most advanced malaria vaccine for P. falciparum (RTS,S, a subunit vaccine containing of a portion of the major sporozoite surface protein) conferred limited protection in Phase III trials, falling short of WHO-established vaccine efficacy goals. However, blocking the sporozoite stage of infection in P. vivax, before the establishment of the chronic liver infection, might be an effective malaria vaccine strategy to reduce the occurrence of relapsing blood stages. It is also thought that a multivalent vaccine comprising multiple sporozoite surface antigens will provide better protection, but a comprehensive analysis of proteins in P. vivax sporozoites is not available. To inform sporozoite-based vaccine development, we employed mass spectrometry-based proteomics to identify nearly 2,000 proteins present in P. vivax salivary gland sporozoites. Analysis of protein post-translational modifications revealed extensive phosphorylation of glideosome proteins as well as regulators of transcription and translation. Additionally, the sporozoite surface proteins CSP and TRAP, which were recently discovered to be glycosylated in P. falciparum salivary gland sporozoites, were also observed to be similarly modified in P. vivax sporozoites. Quantitative comparison of the P. vivax and P. falciparum salivary gland sporozoite proteomes revealed a high degree of similarity in protein expression levels, including among invasion-related proteins. Nevertheless, orthologs with significantly different expression levels between the two species could be identified, as well as highly abundant, species-specific proteins with no known orthologs. Finally, we employed chemical labeling of live sporozoites to isolate and identify 36 proteins that are putatively surface-exposed on P. vivax salivary gland sporozoites. In addition to identifying conserved sporozoite surface proteins identified by similar analyses of other Plasmodium species, our analysis identified several as-yet uncharacterized proteins, including a putative 6-Cys protein with no known ortholog in P. falciparum.
Running oil‐bath chemistry in a microwave! Using reaction vials made out of strongly microwave‐absorbing silicon carbide (SiC) in a microwave reactor simulates experiments conducted in an autoclave ...with conductive heating because of the efficient shielding of the electromagnetic field by the SiC vial. This technology makes it possible to study the significance of microwave effects.
A continuous‐flow process for the in situ on‐demand generation of cyanogen bromide (BrCN) from bromine and potassium cyanide that makes use of membrane‐separation technology is described. In order to ...circumvent the handling, storage, and transportation of elemental bromine, a continuous bromine generator using bromate–bromide synproportionation can optionally be attached upstream. Monitoring and quantification of BrCN generation was enabled through the implementation of in‐line FTIR technology. With the Br2 and BrCN generators connected in series, 0.2 mmol BrCN per minute was produced, which corresponds to a 0.8 m solution of BrCN in dichloromethane. The modular Br2/BrCN generator was employed for the synthesis of a diverse set of biologically relevant five‐ and six‐membered cyclic amidines and guanidines. The set‐up can either be operated in a fully integrated continuous format or, where reactive crystallization is beneficial, in semi‐batch mode.
Cyanogen bromide on tap: The highly toxic but synthetically powerful reagent cyanogen bromide (BrCN) was generated in a fully continuous fashion from benign precursors and directly used for the synthesis of medicinally relevant N‐heterocycles.
This Personal Account describes the author's involvement in the field of microwave‐assisted organic synthesis (MAOS) from the late 1990’s starting out with kitchen microwave ovens right through to ...the development of a reactor in 2016 that – although not using microwave technology – in many ways mimics the performance of a modern laboratory microwave. The reader is taken along a journey that has spanned two decades of intense research on various aspects of microwave chemistry, and, at the same time, was intimately linked to key innovations regarding equipment design and development. A “behind the scenes” approach is taken in this article to share – from a very personal point of view – how specific projects and research ideas were conceived and developed in my research group, and how in general the field of microwave chemistry has progressed in the last two decades.
Microwave chemistry has turned from laboratory curiosity to an accepted technology in the past three decades. While dedicated instrumentation was rather expensive in the early days, current equipment runs at significantly below 10.000 €. This account details advancements in equipment design and development and describes the author's involvement in the field of microwave‐assisted organic synthesis since 1998.
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