Departments of Defense and Agriculture team up to develop new insecticides for mosquito control

Mosquito-borne pathogens are among the most important sources of human disease that cause morbidity and mortality worldwide. They include the viruses responsible for deadly outbreaks of yellow fever, Rift Valley fever, eastern equine encephalitis, Japanese encephalitis and dengue, and an assortment of other serious illnesses caused by the etiological agents of West Nile fever, St Louis encephalitis, Murray Valley encephalitis, Venezuelan equine encephalitis and chikungunya disease. Dengue viruses, of which there are 4 serotypes, cause an estimated 50-100 million new illnesses each year (and 25,000 deaths) while the latest chikungunya epidemic has lasted longer, affected more people, and occurred over a wider geographic area than any previous outbreak of the disease. Yellow fever outbreaks continue to occur sporadically in South America and Africa when either vaccination or vector control are inadequate. These outbreaks have been controlled by creating barrier zones of vaccinated people and by increasing the intensity of vector control. The threat of devastating outbreaks of yellow fever remains, as illustrated by continuing quarantine and vaccination requirements for international travel. The most devastating of all mosquito-borne diseases is malaria, which kills an estimated 1 million people annually, while infecting another 500 million. Although public health efforts have been able to reduce or eliminate vector-borne pathogens in many situations, some parts of the world have actually suffered increases during the past 30 years. A number of agencies have responded to this problem with much increased levels of attention: World Health Organization, Bill and Melinda Gates Foundation, President’s Malaria Initiative, Institute Pasteur, US Centers for Disease Control and Prevention, and US National Institutes of Health. However, morbidity and mortality due to mosquito-borne diseases is increasing. Today, mosquito wars are being fought around the globe and on many fronts. Insecticide-treated bed nets are mass-produced and distributed to the hardesthit malarious regions in Africa, India and southern Asia. Vaccines have been developed to protect humans and domestic animals against Yellow fever, Japanese encephalitis, Rift Valley fever and eastern equine encephalitis, with intensive ongoing research targeting dengue, West Nile virus, and malaria vaccine development. New skin and clothing repellents for personal protection against all biting insects are being developed, and insecticide and related application technology development is in full swing. Of these, the key component for protecting humans from mosquito- borne illness is the use of effective insecticides that quickly kill millions of mosquitoes before they can pass their pathogens to sicken or kill humans. Mosquito adulticides and larvicides are a key component of our assault, along with indoor residual spraying and insecticide-treated bed nets. Unfortunately, mosquitoes are fighting back somewhat successfully by developing resistance to currently used mosquito adulticides. To date at least 100 species of pathogen-carrying mosquitoes have overcome the effects of today’s limited arsenal of adulticides. We now have only 2 chemical classes of adulticides available for adult mosquito control: organophosphates (OPs) and pyrethroids. Malathion is one of our oldest organophosphate adulticides and the workhorse of this class. It was developed in the early 1950s for agricultural pest control and has been used extensively around the world as a mosquito adulticide since 1953. It is a cholinesterase inhibitor that impairs nerve cell transmission. Resistant mosquitoes have at least 3 biochemical processes for detoxifying this class of insecticide. Pyrethroid insecticides were developed in the 1970s as analogs of pyrethrum, a natural product of chrysanthemum flowers, known for its insecticidal properties for hundreds of years. Pyrethroids provide rapid knockdown of mosquitoes by binding to sodium channels on nerve cells and subsequently depolarizing them to stop neural transmission. Resistant mosquitoes are now capable of detoxifying pyrethroids by the above 3 biochemical processes and target cell insensitivity. Larvicides offer more target sites for killing immature mosquitoes, but increased tolerance or resistance has also been reported among different larvicide classes including the stomach poison Bacillus sphaericus, insect growth regulator (methoprene), and a commonly used OP (temephos) among some mosquito species

Natural Toxins for Use in Pest Management

Natural toxins are a source of new chemical classes of pesticides, as well as environmentally and toxicologically safer molecules than many of the currently used pesticides. Furthermore, they often have molecular target sites that are not exploited by currently marketed pesticides. There are highly successful products based on natural compounds in the major pesticide classes. These include the herbicide glufosinate (synthetic phosphinothricin), the spinosad insecticides, and the strobilurin fungicides. These and other examples of currently marketed natural product-based pesticides, as well as natural toxins that show promise as pesticides from our own research are discussed

Fluorine-19 nuclear magnetic resonance investigation of interactions between tryptophan analogs and hemoglobin.

Fluorine-19 nuclear magnetic resonance investigation of interactions between tryptophan analogs and hemoglobin

Antifungal and Phytotoxic Activities of Isolated Compounds from <i>Helietta parvifolia</i> Stems

The identification of natural and environmentally friendly pesticides is a key area of interest for the agrochemical industry, with many potentially active compounds being sourced from numerous plant species. In this study, we report the bioassay-guided isolation and identification of phytotoxic and antifungal compounds from the ethyl acetate extract of Helietta parvifolia stems. We identified eight compounds, consisting of two coumarins and six alkaloids. Among these, a new alkaloid, 2-hydroxy-3,6,7-trimethoxyquinoline-4-carbaldehyde (6), was elucidated, along with seven known compounds. The phytotoxicity of purified compounds was evaluated, and chalepin (4) was active against Agrostis stolonifera at 1 mM with 50% inhibition of seed germination and it reduced Lemna pausicotata (duckweed) growth by 50% (IC50) at 168 μM. Additionally, we evaluated the antifungal activity against the fungal plant pathogen Colletotrichum fragariae using a thin-layer chromatography bioautography assay, which revealed that three isolated furoquinoline alkaloids (flindersiamine (3), kokusagenine (7), and maculine (8)) among the isolated compounds had the strongest inhibitory effects on the growth of C. fragariae at all tested concentrations. Our results indicate that these active natural compounds, i.e., (3), (4), (7), and (8), could be scaffolds for the production of more active pesticides with better physicochemical properties

Bioassay-Guided Isolation and Structure Elucidation of Fungicidal and Herbicidal Compounds from <i>Ambrosia salsola</i> (Asteraceae)

The discovery of potent natural and ecofriendly pesticides is one of the focuses of the agrochemical industry, and plant species are a source of many potentially active compounds. We describe the bioassay-guided isolation of antifungal and phytotoxic compounds from the ethyl acetate extract of Ambrosia salsola twigs and leaves. With this methodology, we isolated and identified twelve compounds (four chalcones, six flavonols and two pseudoguaianolide sesquiterpene lactones). Three new chalcones were elucidated as (S)-&#946;-Hydroxy-2&#8242;,3,4,6&#8242;-tetrahydroxy-5-methoxydihydrochalcone (salsolol A), (S)-&#946;-Hydroxy-2&#8242;,4,4&#8242;,6&#8242;-tetrahydroxy-3-methoxydihydrochalcone (salsolol B), and (R)-&#945;, (R)-&#946;-Dihydroxy-2&#8242;,3,4,4&#8242;,6&#8242;-pentahydroxydihydrochalcone (salsolol C) together with nine known compounds: balanochalcone, six quercetin derivatives, confertin, and neoambrosin. Chemical structures were determined based on comprehensive direct analysis in real time-high resolution mass spectrometry (HR-DART-MS), as well as 1D and 2D NMR experiments: Cosy Double Quantum Filter (DQFCOSY), Heteronuclear Multiple Quantum Coherence (HMQC) and Heteronuclear Multiple Bond Coherence (HMBC), and the absolute configurations of the chalcones were confirmed by CD spectra analysis. Crystal structure of confertin was determined by X-ray diffraction. The phytotoxicity of purified compounds was evaluated, and neoambrosim was active against Agrostis stolonifera at 1 mM, while confertin was active against both, Lactuca sativa and A. stolonifera at 1 mM and 100 &#181;M, respectively. Confertin and salsolol A and B had IC50 values of 261, 275, and 251 &#181;M, respectively, against Lemna pausicotata (duckweed). The antifungal activity was also tested against Colletotrichum fragariae Brooks using a thin layer chromatography bioautography assay. Both confertin and neoambrosin were antifungal at 100 &#181;M, with a higher confertin activity than that of neoambrosin at this concentration

Furanocoumarin with Phytotoxic Activity from the Leaves of (Rutaceae)

Bioassay-guided fractionation of the ethyl acetate extract of leaves was carried out to identify phytotoxic and antifungal constituents. A novel phytotoxic furanocoumarin 8-(3-methylbut-2-enyloxy)-marmesin acetate () and its deacyl analog 8-(3-methylbut-2-enyloxy)-marmesin () were isolated. The X-ray crystal structure determination is reported for the first time for . Both and have the S configuration at C-2\u27 based on X-ray crystallographic data. Both these compounds inhibited the growth of the dicot (lettuce) and the monocot with a more pronounced inhibitory effect on the monocots at 330 μM by . In Hegelm phytotoxicity bioassay, the IC value for was 26 μM, whereas had an IC value of 102 μM. Compounds and were weakly antifungal against Brooks in TLC bioautography