RESUMO
A total of 115 aryl amides were synthesized and screened for vapor repellency against the Orlando (OR) strain of Aedes aegypti mosquitoes. Of these compounds, 29 had 1 h repellency EC50 values comparable to or better than N,N-diethyl-meta-toluamide (DEET, 1 h EC50 value of 35 µg/cm2), with 2,2,3,3,3-pentafluoro-N-(4-fluorophenyl)propenamide (53) and 2,2,3,3,4,4,4-heptafluoro-N-(3,4,5-trifluorophenyl)butanamide (101) exhibiting the most potent EC50 values of 4.5 and 2.9 µg/cm2, respectively. The cross-resistance of select, highly potent, derivatives against the pyrethroid-resistant Puerto Rico (PR) strain of A. aegypti was also investigated, and little to no resistance was observed. When synergized with 1R-trans-permethrinic acid (TFA), compound 101 had a 1 h EC50 value 6 times lower than metofluthrin against OR and 40 times lower against PR mosquitoes. Additionally, preliminary mammalian oral toxicity was screened for compounds 69 and 101, and both exhibited LD50 values of >2000 mg/kg. The structure-activity relationship analysis, which guided the synthesis of these derivatives, is given, and key trends are highlighted to inform future analogue design.
Assuntos
Aedes , Repelentes de Insetos , Animais , DEET/farmacologia , Repelentes de Insetos/farmacologia , Porto Rico , Relação Estrutura-AtividadeRESUMO
Pyrethroids are one of the most commonly used classes of insecticides, and their acid and alcohol components are esterase degradation products, usually considered to be biologically inactive. In this study, it was found that several pyrethroid acids had a spatial repellent activity that was greater than DEET, often more active than the parent pyrethroids, and showed little cross resistance in a pyrethroid-resistant Puerto Rico strain of Aedes aegypti mosquitoes. Further investigation revealed that the acids can synergize not only contact repellent standards but also other pyrethroid components as well as the parent pyrethroids themselves. Synergism by the pyrethroid acids is expressed as both increased spatial repellency and vapor toxicity as well as human bite protection. Electrophysiological studies confirmed that pyrethroid acids (100 µM) had no effect on neuronal discharge in larval Drosophila melanogaster CNS and were detected by electroantennography, and there was little resistance to olfactory sensing of these acids in antennae from Puerto Rico strain mosquitoes carrying kdr mutations. Thus, the data suggest that the pyrethroid acids have a different mode of action than the parent pyrethroids, unrelated to the voltage-sensitive sodium channel. The results highlight the potential of pyrethroid acids to be useful in future repellent formulations.
Assuntos
Aedes/efeitos dos fármacos , Repelentes de Insetos/toxicidade , Piretrinas/química , Piretrinas/toxicidade , Ácidos/química , Ácidos/toxicidade , Aedes/genética , Álcoois/química , Álcoois/toxicidade , Animais , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/crescimento & desenvolvimento , Sinergismo Farmacológico , Repelentes de Insetos/química , Resistência a Inseticidas , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Estrutura Molecular , Controle de Mosquitos , Porto RicoRESUMO
BACKGROUND: El Niño/Southern Oscillation (ENSO) related climate anomalies have been shown to have an impact on infectious disease outbreaks. The Climate Prediction Center of the National Oceanic and Atmospheric Administration (NOAA/CPC) has recently issued an unscheduled El Niño advisory, indicating that warmer than normal sea surface temperatures across the equatorial eastern Pacific may have pronounced impacts on global tropical precipitation patterns extending into the northern hemisphere particularly over North America. Building evidence of the links between ENSO driven climate anomalies and infectious diseases, particularly those transmitted by insects, can allow us to provide improved long range forecasts of an epidemic or epizootic. We describe developing climate anomalies that suggest potential disease risks using satellite generated data. RESULTS: Sea surface temperatures (SSTs) in the equatorial east Pacific ocean have anomalously increased significantly during July - October 2006 indicating the typical development of El Niño conditions. The persistence of these conditions will lead to extremes in global-scale climate anomalies as has been observed during similar conditions in the past. Positive Outgoing Longwave Radiation (OLR) anomalies, indicative of severe drought conditions, have been observed across all of Indonesia, Malaysia and most of the Philippines, which are usually the first areas to experience ENSO-related impacts. This dryness can be expected to continue, on average, for the remainder of 2006 continuing into the early part of 2007. During the period November 2006 - January 2007 climate forecasts indicate that there is a high probability for above normal rainfall in the central and eastern equatorial Pacific Islands, the Korean Peninsula, the U.S. Gulf Coast and Florida, northern South America and equatorial east Africa. Taking into consideration current observations and climate forecast information, indications are that the following regions are at increased risk for disease outbreaks: Indonesia, Malaysia, Thailand and most of the southeast Asia Islands for increased dengue fever transmission and increased respiratory illness; Coastal Peru, Ecuador, Venezuela, and Colombia for increased risk of malaria; Bangladesh and coastal India for elevated risk of cholera; East Africa for increased risk of a Rift Valley fever outbreak and elevated malaria; southwest USA for increased risk for hantavirus pulmonary syndrome and plague; southern California for increased West Nile virus transmission; and northeast Brazil for increased dengue fever and respiratory illness. CONCLUSION: The current development of El Niño conditions has significant implications for global public health. Extremes in climate events with above normal rainfall and flooding in some regions and extended drought periods in other regions will occur. Forecasting disease is critical for timely and efficient planning of operational control programs. In this paper we describe developing global climate anomalies that suggest potential disease risks that will give decision makers additional tools to make rational judgments concerning implementation of disease prevention and mitigation strategies.
Assuntos
Clima , Infecções/etiologia , África , Ásia , Austrália , Surtos de Doenças , Humanos , Infecções/epidemiologia , Fatores de Risco , América do Sul , Estados Unidos , Tempo (Meteorologia)RESUMO
Entre 1950 e 1998 houve surtos de febre no Vale do Rift, no Quênia, após períodos de aumentos pluviométricos anormais. Em escala interanual, esses períodos estiveram associados à fase quente do fenômeno ENSO (El Niño/Southern Oscillation) na Africa Oriental. As chuvas alagam os criadouros de mosquitos - dambos -, cujos ovos, infectados pela via transovariana, eclodem, produzindo mosquitos Aedes, transmissores do vírus da febre do Vale do Rift aos seres humanos e, em especial, ao gado. A análise dos dados históricos sobre surtos de febre do Vale do Rift e indicadores do fenômeno ENSO - incluindo temperaturas superficiais dos Oceanos Pacífico e Indico e o Indice de Oscilaçäo Sul - mostrou que mais de 75 por cento dos surtos ocorreram em períodos quentes do ENSO. Na época estudada - 1981-1998 -, o mapeamento das condiçöes ecológicas via satélite (NDVI) - com dados normalizados sobre diferenças na vegetaçäo - evidenciou que as áreas de surto apresentaram desvios anômalos na intensidade do verde da vegetaçäo (indicador de pluviosidade alta), em particular, nas regiöes áridas da Africa Oriental - as mais afetadas pela febre. Os resultados indicam associaçäo estreita entre variabilidade climática interanual e surtos de febre do Vale do Rift no Quênia.