Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure-activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress

Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies

Toward the integrated marine debris observing system

Plastics and other artificial materials pose new risks to the health of the ocean. Anthropogenic debris travels across large distances and is ubiquitous in the water and on shorelines, yet, observations of its sources, composition, pathways, and distributions in the ocean are very sparse and inaccurate. Total amounts of plastics and other man-made debris in the ocean and on the shore, temporal trends in these amounts under exponentially increasing production, as well as degradation processes, vertical fluxes, and time scales are largely unknown. Present ocean circulation models are not able to accurately simulate drift of debris because of its complex hydrodynamics. In this paper we discuss the structure of the future integrated marine debris observing system (IMDOS) that is required to provide long-term monitoring of the state of this anthropogenic pollution and support operational activities to mitigate impacts on the ecosystem and on the safety of maritime activity. The proposed observing system integrates remote sensing and in situ observations. Also, models are used to optimize the design of the system and, in turn, they will be gradually improved using the products of the system. Remote sensing technologies will provide spatially coherent coverage and consistent surveying time series at local to global scale. Optical sensors, including high-resolution imaging, multi- and hyperspectral, fluorescence, and Raman technologies, as well as SAR will be used to measure different types of debris. They will be implemented in a variety of platforms, from hand-held tools to ship-, buoy-, aircraft-, and satellite-based sensors. A network of in situ observations, including reports from volunteers, citizen scientists and ships of opportunity, will be developed to provide data for calibration/validation of remote sensors and to monitor the spread of plastic pollution and other marine debris. IMDOS will interact with other observing systems monitoring physical, chemical, and biological processes in the ocean and on shorelines as well as the state of the ecosystem, maritime activities and safety, drift of sea ice, etc. The synthesized data will support innovative multi-disciplinary research and serve a diverse community of users

Mitigating the risk of arsenic and fluoride contamination of groundwater through a multi-model framework of statistical assessment and natural remediation techniques

The present book chapter discusses the mechanism of Arsenic and Fluoride release in the groundwater and its related toxicity. The use of spatial modelling techniques involving machine learning classification algorithms can help predict the concentration in binary outputs. The variability in the cause of occurrence of Arsenic forces researchers to try different adsorption materials that could help decrease the concentration levels of contaminants to permissible levels. The co-occurrence of Fluoride and Arsenic at places complicates both prediction as well as remediation. Therefore a multi-model technique involving statistical assessment and natural remediation is required to be used in tandem.by Ashwin Singh, Arbind Kumar Patel and Manish Kuma