Agrochemicals against Malaria, Sleeping Sickness, Leishmaniasis and Chagas Disease

Abstract

In tropical regions, protozoan parasites can cause severe diseases with malaria, leishmaniasis, sleeping sickness, and Chagas disease standing in the forefront. Many of the drugs currently being used to treat these diseases have been developed more than 50 years ago and can cause severe adverse effects. Above all, resistance to existing drugs is widespread and has become a serious problem threatening the success of control measures. In order to identify new antiprotozoal agents, more than 600 commercial agrochemicals have been tested on the pathogens causing the above mentioned diseases. For all of the pathogens, compounds were identified with similar or even higher activities than the currently used drugs in applied in vitro assays. Furthermore, in vivo activity was observed for the fungicide/oomyceticide azoxystrobin, and the insecticide hydramethylnon in the Plasmodium berghei mouse model, and for the oomyceticide zoxamide in the Trypanosoma brucei rhodesiense STIB900 mouse model, respectively.

Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm

“…Tolfenpyrad was included in the MMV ‘Pathogen Box’ based on results from a compound screen of agro-chemicals, which showed that tolfenpyrad has potent and selective in vitro activity against Trypanosoma spp. (Witschel et al., 2012). As a pesticide, tolfenpyrad has relatively broad activity against egg, larval, nymphal and adult stages of various arthropods (including Hemiptera, Coleoptera, Diptera, Lepidoptera, Thysanoptera and Acarina), and has been applied to various infested crops (Song et al., 2012, Yamaguchi et al., 2012).…”

“…Currently, there are no commercial vaccines available against most of these diseases (Pedrique et al., 2013, Hotez et al., 2016), diagnostic methods frequently suffer from insufficient specificity and sensitivity (Utzinger et al., 2012, Assefa et al., 2014), and treatments are often not highly effective and/or are toxic (Castro et al., 2006, Witschel et al., 2012, Molina et al., 2015). In addition, often the small numbers of drugs (or drug classes) frequently used, limited use of combination drug therapies and the implementation of mass drug administration programs bear the risk of drug resistance emerging in some groups of target pathogens (Humphries et al., 2012, Witschel et al., 2012, Webster et al., 2014). Therefore, the development of new drugs is crucial to ensure effective and sustained treatment and control into the future.…”

Potential of agricultural fungicides for antifungal drug discovery

“…One of the exceptions is fluconazole, a fungicide product discovered by the pharmaceutical sector that is now used as a pharmaceutical but also was patented as a chemical with applications in crop production. [29][30][31][32][33][34] Bioavailability is highly important for any bioactive agent. The Lipinski's Rule of Five [35] can be considered as the reference for defining physicochemical and structural parameters for oral drug bioavailability.…”

Pseudiline: halogenierte, allosterische Inhibitoren des Enzyms IspD aus dem Mevalonat‐unabhängigen Biosyntheseweg

“…Um beide Felder zu bearbeiten, wurden Leitstrukturen aus der agrochemischen Forschung gegen infektiçse Keime getestet. [3] Während Säugetiere ausschließlich den Mevalonat-abhängigen Biosyntheseweg zu den Terpenoidvorstufen Isopentenyldiphosphat (IPP) und Dimethylallyldiphosphat (DMAPP) verwenden, [4] benutzen Pflanzen und viele humane Pathogene den Mevalonat-unabhängigen (auch 1-Desoxy-d-xylulose-5-phosphat (DXP) genannten) Biosyntheseweg, der in den 1990er Jahren entdeckt wurde.…”

“…[12] Darüber hinaus wurden diese Derivate in vitro auf ihre Wirksamkeit gegen Plasmodium falciparum getestet. Die herbizide Aktivität der Pseudiline wurde bereits beschrieben, [3] und hier werden deren allosterische Bindungseigenschaften auf atomarer Ebene mittels Rçntgen-kristallographie an AtIspD-Komplexstrukturen aufgezeigt, wobei effektive Protein-Ligand-Halogenbindungsinteraktionen gefunden wurden.…”