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1.
J Am Chem Soc ; 142(8): 3762-3774, 2020 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-31910623

RESUMEN

The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds provides access to diverse structural analogs and expands synthetically-accessible chemical space. We report a C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta position. This protocol is also amenable to distal structural modifications of α-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd-Ag transition structure is essential for product formation in the ß-bromide elimination step.


Asunto(s)
Alquinos/química , Preparaciones Farmacéuticas/química , Productos Biológicos/química , Estructura Molecular
2.
J Theor Biol ; 488: 110117, 2020 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-31866397

RESUMEN

West Nile virus (WNV) is an arthropod-borne virus (arbovirus) transmitted by the bites of infected mosquitoes. WNV can also infect horses and humans, where it may cause serious illness and can be fatal. Birds are the natural reservoir, and humans, equines and probably other mammals are dead-end hosts. In 2018, WNV occurred for the first time in Germany, affecting birds and horses. Seroconversion of an exposed veterinarian has also been reported. It is therefore of importance to evaluate the circumstances, under which WNV may establish in Germany as a whole or in particular favourable regions. In our current work, we formulate a dynamic model to describe the spreading process of West Nile virus in the presence of migratory birds. To investigate the possible role of migratory birds in the dissemination of WNV in Germany, we include the recurring presence of migratory birds through a mechanistic ordinary differential equations (ODE) model system. We also perform a sensitivity analysis of the infection curves. Seasonal impacts are also taken into consideration. As result, we present an analytical expression for the basic reproduction number R0. We find that after introducing WNV into Germany, R0 will be above the critical value in many regions of the country. Furthermore, we observe that in the south of Germany, the disease reoccurs in the following season after the introduction. We include a potential distribution map associated with WNV cases in Germany to illustrate our findings in a spatial scale.


Asunto(s)
Culex , Fiebre del Nilo Occidental , Virus del Nilo Occidental , Animales , Alemania/epidemiología , Caballos , Modelos Teóricos , Temperatura , Fiebre del Nilo Occidental/epidemiología , Fiebre del Nilo Occidental/veterinaria
3.
Chemistry ; 25(40): 9433-9437, 2019 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-30977181

RESUMEN

Deuterium-labeled compounds find wide applications in kinetic studies, and within the pharmaceutical industry. An easily removable pyrimidine-based auxiliary has been employed for the meta-C-H deuteration of arenes. The scope of this Pd-catalyzed deuteration using commercially available [D1 ]- and [D4 ]-acetic acid has been demonstrated by its application in phenylacetic acid and phenylmethanesulfonate derivatives. A detailed mechanistic study led us to explore the reversibility of the non-rate determining C-H activation step. The present study of meta-deuterium incorporation illustrates the template morphology in terms of selectivity. The applicability of this method has been demonstrated by the selective deuterium incorporation into various pharmaceuticals.

4.
Acta Trop ; 258: 107346, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39111645

RESUMEN

West Nile virus (WNV) is prevalent across the United States, but its transmission patterns and spatio-temporal intensity vary significantly, particularly in the Eastern United States. For instance, Chicago has long been a hotspot for WNV cases due to its high cumulative incidence of infection, with the number of cases varying considerably from year to year. The abilities of host species to maintain and disseminate WNV, along with eco-epidemiological factors that influence vector-host contact rates underlie WNV transmission potential. There is growing evidence that several vectors exhibit strong feeding preferences towards different host communities. In our research study, we construct a process based weather driven ordinary differential equation (ODE) model to understand the impact of one vector species (Culex pipiens), its preferred avian and non-preferred human hosts on the basic reproduction number (R0). In developing this WNV transmission model, we account for the feeding index, which is defined as the relative preference of the vectors for taking blood meals from a competent avian host versus a non-competent mammalian host. We also include continuous introduction of infected agents into the model during the simulations as the introduction of WNV is not a single event phenomenon. We derive an analytic form of R0 to predict the conditions under which there will be an outbreak of WNV and the relationship between the feeding index and the efficacy of adulticide is highly nonlinear. In our mechanistic model, we also demonstrate that adulticide treatments produced significant reductions in the Culex pipiens population. Sensitivity analysis demonstrates that feeding index and rate of introduction of infected agents are two important factors beside the efficacy of adulticide. We validate our model by comparing simulations to surveillance data collected for the Culex pipiens complex in Cook County, Illinois, USA. Our results reveal that the interaction between the feeding index and mosquito abatement strategy is intricate, especially considering the fluctuating temperature conditions. This induces heterogeneous transmission patterns that need to be incorporated when modelling multi-host, multi-vector transmission models.


Asunto(s)
Culex , Conducta Alimentaria , Mosquitos Vectores , Temperatura , Fiebre del Nilo Occidental , Virus del Nilo Occidental , Animales , Virus del Nilo Occidental/fisiología , Fiebre del Nilo Occidental/transmisión , Culex/virología , Culex/fisiología , Humanos , Mosquitos Vectores/virología , Mosquitos Vectores/fisiología , Modelos Teóricos , Aves/virología , Número Básico de Reproducción , Control de Mosquitos/métodos
5.
Chem Commun (Camb) ; 60(15): 2054-2057, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38288529

RESUMEN

The palladium-catalyzed oxidative C3-alkenylation of anthranils (2,1-benzisoxazoles) with various styrenes has been successfully achieved. The C3-alkenylated anthranils were subsequently utilized in a [4+2]-cycloaddition with in situ generated α,ß-unsaturated ketones leading to the synthesis of a diverse range of olefin-containing quinolines. Notably, this reaction exclusively yielded mono-alkenylated products with E-selectivity. The optimized catalytic conditions were compatible with a wide variety of substituted olefins and anthranils, forming various C3-alkenylated anthranils with good yields. To showcase the application of the present methodology, the C3-alkenylated anthranils have been employed as synthons to access a wide range of substituted quinolines.

6.
ArXiv ; 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39398219

RESUMEN

Even as the incidence of mosquito-borne diseases like West Nile Virus (WNV) in North America has risen over the past decade, effectively modelling mosquito population density or, the abundance has proven to be a persistent challenge. It is critical to capture the fluctuations in mosquito abundance across seasons in order to forecast the varying risk of disease transmission from one year to the next. We develop a process-based mechanistic weather-driven Ordinary Differential Equation (ODE) model to study the population biology of both aqueous and terrestrial stages of mosquito population. The progression of mosquito lifecycle through these stages is influenced by different factors, including temperature, daylight hours, intra-species competition and the availability of aquatic habitats. Weather-driven parameters are utilised in our work, are a combination of laboratory research and literature data. In our model, we include precipitation data as a substitute for evaluating additional mortality in the mosquito population. We compute the \textit{Basic offspring number} of the associated model and perform sensitivity analysis. Finally, we employ our model to assess the effectiveness of various adulticides strategies to predict the reduction in mosquito population. This enhancement in modelling of mosquito abundance can be instrumental in guiding interventions aimed at reducing mosquito populations and mitigating mosquito-borne diseases such as the WNV.

7.
Chem Commun (Camb) ; 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39397744

RESUMEN

Autocatalytic and DMSO-participating regioselective synthesis of N,N-disubstituted pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones from anilines and barbituric acids has been achieved. In this newly developed one-pot tandem reaction, DMSO serves as a solvent cum methine source. Additionally, barbituric acid plays a dual role by acting as a substrate and a catalyst, making this reaction an environmentally benign approach to accessing valuable heterocycles. This method offers an auto-catalytic, additive-free, and operationally simple approach with a wide substrate scope and excellent tolerance for various functional groups. Furthermore, a few controlled experiments were conducted to gain insight into the reaction mechanism. Moreover, large-scale experiments have further enriched this methodology.

8.
Prev Vet Med ; 224: 106101, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38244415

RESUMEN

Our study explored the patterns of bovine brucellosis dissemination in Minas Gerais state, Brazil, by examining data on passive surveillance of bovine brucellosis cases from the Instituto Mineiro de Agropecuaria (IMA) (Animal Health Authority), as well as cattle population and bovine brucellosis testing, from 2011 to 2018 by means of a spatiotemporal analysis. We plotted cases, populations and testing distributions and performed spatial autocorrelation (Moran's I test) and local indicators of spatial autocorrelation (LISA) analyses. Moreover, we assessed the correlation of the spatial distribution and the compiled data (brucellosis cases, cattle populations, and brucellosis testing) by Lee's test. Our results showed that bovine brucellosis cases occurred mainly in the Triângulo Mineiro, Alto Paranaíba and Northwest regions, which reported cases in all analyzed years (2011 to 2018). The cattle population of Minas Gerais was concentrated in the same regions as bovine brucellosis cases, and the performed tests through the analyzed years (2011 to 2018). Moran's I test results of the case data showed significant spatial autocorrelation in 2011, 2015 and 2018 (p value < 0.05), and from 2011 to 2018, the population and testing data were also significant in Moran's I test (p value < 0.01). The results of cluster analysis (LISA) of cases showed clusters mainly in the Triângulo Mineiro, Alto Paranaíba, Northwest and South regions in 2011, 2015 and 2018. The local clusters for cattle populations and brucellosis testing were also observed in the same regions as bovine brucellosis cases in all years (2011 to 2018). The correlation results between clusters (Lee's test) were 0.22 (p value < 0.01) in 2011, 0.15 (p value < 0.01) in 2015 and 0.43 (p value <0.01) in 2018 between cases and populations, and 0.25 (p value <0.01) in 2011, 0.14 (p value <0.01) in 2015 and 0.38 (p value < 0.01) in 2018 for testing and cases. Therefore, our results showed that brucellosis cases were distributed together with cattle populations and brucellosis testing data, indicating that brucellosis in cattle in Minas Gerais state is being identified where there are more animals and where more tests are performed.


Asunto(s)
Brucelosis Bovina , Brucelosis , Enfermedades de los Bovinos , Bovinos , Animales , Brasil/epidemiología , Brucelosis Bovina/epidemiología , Brucelosis/epidemiología , Brucelosis/veterinaria , Análisis Espacio-Temporal , Análisis Espacial , Enfermedades de los Bovinos/epidemiología
9.
Biosystems ; 224: 104827, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36626949

RESUMEN

After the detection of coronavirus disease 2019 (Covid-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, Hubei Province, China in late December, the cases of Covid-19 have spiralled out around the globe. Due to the clinical similarity of Covid-19 with other flulike syndromes, patients are assayed for other pathogens of influenza like illness. There have been reported cases of co-infection amongst patients with Covid-19. Bacteria for example Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumonia, Legionella pneumophila etc and viruses such as influenza, coronavirus, rhinovirus/enterovirus, parainfluenza, metapneumovirus, influenza B virus etc are identified as co-pathogens. In our current effort, we develop and analysed a compartmental based Ordinary Differential Equation (ODE) type mathematical model to understand the co-infection dynamics of Covid-19 and other influenza type illness. In this work we have incorporated the saturated treatment rate to take account of the impact of limited treatment resources to control the possible Covid-19 cases. As results, we formulate the basic reproduction number of the model system. Finally, we have performed numerical simulations of the co-infection model to examine the solutions in different zones of parameter space.


Asunto(s)
COVID-19 , Coinfección , Gripe Humana , Infecciones del Sistema Respiratorio , Virosis , Virus , Humanos , SARS-CoV-2 , Gripe Humana/epidemiología , Gripe Humana/diagnóstico , COVID-19/epidemiología , Coinfección/epidemiología , Coinfección/diagnóstico , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/microbiología , Modelos Teóricos
10.
Epidemiologia (Basel) ; 3(1): 116-134, 2022 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-36417271

RESUMEN

Crimean-Congo haemorrhagic fever (CCHF) is a zoonotic disease caused by the Crimean-Congo hemorrhagic fever virus (CCHFV). Ticks of the genus Hyalomma are the main vectors and represent a reservoir for the virus. CCHF is maintained in nature in an endemic vertebrate-tick-vertebrate cycle. The disease is prevalent in wide geographical areas including Asia, Africa, South-Eastern Europe and the Middle East. It is of great importance for the public health given its occasionally high case/fatality ratio of CCHFV in humans. Climate change and the detection of possible CCHFV vectors in Central Europe suggest that the establishment of the transmission in Central Europe may be possible in future. We have developed a compartment-based nonlinear Ordinary Differential Equation (ODE) system to model the disease transmission cycle including blood sucking ticks, livestock and human. Sensitivity analysis of the basic reproduction number R0 shows that decreasing the tick survival time is an efficient method to control the disease. The model supports us in understanding the influence of different model parameters on the spread of CCHFV. Tick-to-tick transmission through co-feeding and the CCHFV circulation through transstadial and transovarial transmission are important factors to sustain the disease cycle. The proposed model dynamics are calibrated through an empirical multi-country analysis and multidimensional plot reveals that the disease-parameter sets of different countries burdened with CCHF are different. This information may help decision makers to select efficient control strategies.

11.
Nat Commun ; 12(1): 1393, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33654108

RESUMEN

Despite the widespread applications of C-H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing groups (DGs) served as ancillary ligands to ensure ortho-, meta- and para-C-H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C-H functionalization: introduction of DG prior to C-H activation and removal of DG post-functionalization. Here we report a temporary directing group (TDG) for meta-C-H functionalization via reversible imine formation. By overruling facile ortho-C-H bond activation by imine-N atom, a suitably designed pyrimidine-based TDG successfully delivered selective meta-C-C bond formation. Application of this temporary directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the meta position has been explored.

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