The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.

With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino–thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure–activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent respiration.

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

No abstract

During the years 2012-2016, the Dutch National Food Consumption survey was conducted in the Netherlands. For the survey, a random sample was drawn from consumer panels stratified by age and gender and maintained representative to the population with regard to region, address density and educational level. Complete results were obtained for 4,313 persons (response rate 65%); including toddlers, children, adolescents, adults and elderly. Pregnant or lactating women were excluded, as well as institutionalised persons. Two non-consecutive GloboDiet 24-hour dietary recalls were conducted by trained dieticians; for participants aged 1-8 and 71-79 years in combination with a food diary. Persons aged 16-70 years were interviewed by telephone. Other participants were interviewed at least once at home; children until age of 16 years and their caretakers were interviewed together. A questionnaire including physical activity and food frequency questions was also administered. Height and weight were measured for the participants that were interviewed at home and self-reported for those interviewed by telephone. The food consumption data were coded into the FoodEx2 nomenclature. Largely, the methodology followed the 2009 Guidance of EFSA on "General principles for the collection of national food consumption data in the view of a pan-European dietary survey". The main deviations concerned the exclusion of infants, not measuring height and weight in all age groups but having it self-reported, performing the interviews by telephone in most age groups, and performing a different dietary assessment method among children younger than 10 years and those above 70 years. The main challenge faced during the fieldwork was the response rate, and during data handling the laborious work necessary to match the >40,000 different reported foods to the national food composition database and the FoodEx2 classification and description system. Given the availability of new technologies, like apps and barcode scanners to identify foods with barcodes it is worthwhile to do research on less labour intensive alternatives for collecting food consumption data, while maintaining the level of detail and harmonisation across Europe.