1-Methyl-1-pyrazole-5-carboxamide Derivatives Exhibit Unexpected Acute Mammalian Toxicity.

A series of 1-methyl-1-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, . These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progressed to an acute toxicity study in a rodent model. Strikingly, acute toxicity was observed in mice.

Human Aurora kinase inhibitor Hesperadin reveals epistatic interaction between Plasmodium falciparum PfArk1 and PfNek1 kinases.

Mitosis has been validated by numerous anti-cancer drugs as being a druggable process, and selective inhibition of parasite proliferation provides an obvious opportunity for therapeutic intervention against malaria. Mitosis is controlled through the interplay between several protein kinases and phosphatases. We show here that inhibitors of human mitotic kinases belonging to the Aurora family inhibit P.

Evaluation of the productive characteristics of the Caqueteño Creole cattle breed.

The objective of this research was to evaluate the productive and reproductive characteristics of the Caqueteño Creole cattle breed. Data was taken from 655 animals organized into 6 groups: group 1 (n = 185), pure Caqueteño Creole cattle breed (Caqueteño); group 2 (n = 34), Caqueteño Creole cattle breed crossing for multiracial animals (Caqueteño 50% × multiracial 50%); group 3 (n = 10) (Caqueteño 75% × Bos indicus 25%); group 4 (n = 56), crossbreed F1 (Bos taurus × B. indicus); group 5 (n = 168), animals with B.

Interaction of Plasmodium falciparum casein kinase 1 with components of host cell protein trafficking machinery.

A pool of Plasmodium falciparum casein kinase 1 (PfCK1) has been shown to localize to the host red blood cell (RBC) membrane and be secreted to the extracellular medium during trophozoite stage of development. We attempted to identify mechanisms for secretion of PfCK1 and its appearance on the RBC membrane. We found that two host proteins with established functions in membrane trafficking in higher eukaryotes, GTPase-activating protein and Vps9 domain-containing protein 1 (GAPVD1), and Sorting nexin 22, consistently co-purify with PfCK1, suggesting that the parasite utilizes trafficking pathways previously thought to be inactive in RBCs.

Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of In Vitro.

Kava extract, an aqueous rhizome emulsion of the plant , has been used for centuries by Pacific Islanders as a ceremonial beverage, and has been sold as an anxiolytic agent for some decades. Kavalactones are a major constituent of kava extract. In a previous investigation, we had identified three kavalactones that inhibit larval development of in an in vitro-bioassay.

Synthesis and structure-activity relationship study of pyrrolidine-oxadiazoles as anthelmintics against Haemonchus contortus.

Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms.

Identification of Fromiamycalin and Halaminol A from Australian Marine Sponge Extracts with Anthelmintic Activity against .

There is an urgent need to discover and develop new anthelmintics for the treatment of parasitic nematodes of veterinary importance to circumvent challenges linked to drug resistant parasites. Being one of the most diverse natural ecosystems, the marine environment represents a rich resource of novel chemical entities. This study investigated 2000 extracts from marine invertebrates, collected from Australian waters, for anthelmintic activity.

Anti- activity of ethoxzolamide.

Ethoxzolamide (EZA), acetazolamide, and methazolamide are clinically used sulphonamide drugs designed to treat non-bacteria-related illnesses (e.g. glaucoma), but they also show antimicrobial activity against the gastric pathogen EZA showed the highest activity, and was effective against clinical isolates resistant to metronidazole, clarithromycin, and/or amoxicillin, suggesting that EZA kills mechanisms different from that of these antibiotics.

Geographical trends of chikungunya and Zika in the Colombian Amazonian gateway department, Caqueta, 2015-2018 - Implications for public health and travel medicine.

Background: Chikungunya (CHIKV) and Zika (ZIKV) significantly affected Latin America in the period 2015-2017. Most studies were reported from urban areas of Brazil and Colombia. In this paper we estimate Incidence rates for CHIKV and ZIKV in Caqueta, the Amazonian gateway area of Colombia, from 2015 to 2018.

Epidemiology of zoonotic tick-borne diseases in Latin America: Are we just seeing the tip of the iceberg?

Ticks are responsible for transmission of multiple bacterial, parasitic and viral diseases. Tick-borne diseases (TBDs) occur particularly in tropical and also subtropical areas. The frequency of these TBDs has been increasing and extending to new territories in a significant way, partly since ticks' populations are highly favored by prevailing factors such as change in land use patterns, and climate change.

An appraisal of natural products active against parasitic nematodes of animals.

Here, the scientific and patent literature on the activities of purified natural compounds has been reviewed, with the aim of assessing their suitability as anthelmintic drug discovery starting points. Only compounds described as active against parasitic nematodes of animals or against the model nematode Caenorhabditis elegans have been analysed. Scientific articles published since 2010 and patents granted from 2000, both inclusive, have been included in this analysis.

Selected α-pyrones from the plants Cryptocarya novoguineensis (Lauraceae) and Piper methysticum (Piperaceae) with activity against Haemonchus contortus in vitro.

Due to the widespread occurrence and spread of anthelmintic resistance, there is a need to develop new drugs against resistant parasitic nematodes of livestock animals. The Nobel Prize-winning discovery and development of the anti-parasitic drugs avermectin and artemisinin has renewed the interest in exploring natural products as anthelmintics. In the present study, we screened 7500 plant extracts for in vitro-activity against the barber's pole worm, Haemonchus contortus, a highly significant pathogen of ruminants.

Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro.

In the present study, the anthelmintic activity of a human tyrosine kinase inhibitor, AG-1295, and 14 related tetrahydroquinoxaline analogues against Haemonchus contortus was explored. These compounds were screened against parasitic larvae - exsheathed third-stage (xL3) and fourth-stage (L4) - using a whole-organism screening assay. All compounds were shown to have inhibitory effects on larval motility, development and growth, and induced evisceration through the excretory pore in xL3s.

Structure-Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development.

Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC value of 0.03 μM while displaying good selectivity, with an IC of 37.9 μM for cytotoxicity.

Optimization of Novel 1-Methyl-1 H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm.

A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR).

Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro.

Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae.

Functional screening of selective mitochondrial inhibitors of Plasmodium.

Phenotypic screening has produced most of the new chemical entities currently in clinical development for malaria, plus many lead compounds active against Plasmodium falciparum asexual stages. However, lack of knowledge about the mode of action of these compounds delays and may even hamper their future development. Identifying the mode of action of the inhibitors greatly helps to prioritise compounds for further development as novel antimalarials.

Parasites under the Spotlight: Applications of Vibrational Spectroscopy to Malaria Research.

New technologies to diagnose malaria at high sensitivity and specificity are urgently needed in the developing world where the disease continues to pose a huge burden on society. Infrared and Raman spectroscopy-based diagnostic methods have a number of advantages compared with other diagnostic tests currently on the market. These include high sensitivity and specificity for detecting low levels of parasitemia along with ease of use and portability.

Multispectral Atomic Force Microscopy-Infrared Nano-Imaging of Malaria Infected Red Blood Cells.

Atomic force microscopy-infrared (AFM-IR) spectroscopy is a powerful new technique that can be applied to study molecular composition of cells and tissues at the nanoscale. AFM-IR maps are acquired using a single wavenumber value: they show either the absorbance plotted against a single wavenumber value or a ratio of two absorbance values. Here, we implement multivariate image analysis to generate multivariate AFM-IR maps and use this approach to resolve subcellular structural information in red blood cells infected with Plasmodium falciparum at different stages of development.

Malaria Parasites in a Hungry Host: Kinases and Host Caloric Restriction Brought Together.

A study recently published in Nature links reduced calorie nutritional intake of host mice with (i) reduced severity of cerebral malaria, (ii) decreased parasitemia, and (iii) activation of a nutrient-sensing pathway that regulates the parasite's proliferation rate. Here, we discuss these findings in the context of human malaria pathology and Plasmodium kinomics.

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

The ins and outs of phosphosignalling in Plasmodium: Parasite regulation and host cell manipulation.

Signal transduction and kinomics have been rapidly expanding areas of investigation within the malaria research field. Here, we provide an overview of phosphosignalling pathways that operate in all stages of the Plasmodium life cycle. We review signalling pathways in the parasite itself, in the cells it invades, and in other cells of the vertebrate host with which it interacts.

Two-dimensional single-cell patterning with one cell per well driven by surface acoustic waves.

In single-cell analysis, cellular activity and parameters are assayed on an individual, rather than population-average basis. Essential to observing the activity of these cells over time is the ability to trap, pattern and retain them, for which previous single-cell-patterning work has principally made use of mechanical methods. While successful as a long-term cell-patterning strategy, these devices remain essentially single use.