Cinnamaldehyde derivatives were synthesized in good to excellent yields in one step by a mild and selective, base-free palladium(II)-catalyzed oxidative Heck reaction starting from acrolein and various arylboronic acids. Prepared α,β-unsaturated aldehydes were used for synthesis of novel α-aryl substituted fosmidomycin analogues, which were evaluated for their inhibition of Mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate reductoisomerase. IC₅₀ values between 0.8 and 27.3 μM were measured. The best compound showed activity comparable to that of the most potent previously reported α-aryl substituted fosmidomycin-class inhibitor.

Influence of distribution and abundance of bacterial taxa on ecosystem function are poorly understood for natural microbial communities. We related 16S rRNA-based terminal restriction fragment length polymorphism to bacterial production and arginine uptake kinetics to test if functional features of bacterioplankton in four lakes could be predicted from community composition. Maximum arginine uptake rate (arginine V_max) ranged from 10% to 100% of bacterial production. Owing to high growth efficiencies on arginine (63–77%), the bacterial community could potentially saturate its carbon demand using this single organic substrate, for example, during sudden surges of free amino acids. However, due to low in situ concentrations of arginine in these lakes (<0.9 g l^-1), actual uptake rates at ambient concentrations rarely exceeded 10% of V_max. Bacterial production and arginine V_max could be predicted from a subset of bacterial ribotypes, tentatively affiliated with several bacterial divisions (Cyanobacteria, Actinobacteria, Bacteroidetes and Proteobacteria). Multivariate statistical analysis indicates that there were both highly important and less important ribotypes for the prediction of bacterial production and arginine V_max. These populations were either negatively or positively related to the respective functional feature, indicating contrasting ecological roles. Our study provides a statistically robust demonstration that, apart from environmental conditions, patterns in bacterial community composition can also be used to predict lake ecosystem function.

Protease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of a potent new agonist, suggested by molecular modelling to bind in the putative orthosteric site, and two novel PAR2 antagonists with distinctly different mechanisms of inhibition. We identify coupling between different PAR2 binding sites. One antagonist is a competitive inhibitor that binds to the orthosteric site, while a second antagonist is a negative allosteric modulator that binds at a remote site. The allosteric modulator shows probe dependence, more effectively inhibiting peptide than protease activation of PAR2 signalling. Importantly, both antagonists are active in vivo, inhibiting PAR2 agonist-induced acute paw inflammation in rats and preventing activation of mast cells and neutrophils. These results highlight two distinct mechanisms of inhibition that potentially could be targeted for future development of drugs that modulate PAR2.

Based on an imidazo[1,2-a]pyridine hit from a high-throughput screening directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a number of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC₅₀ = 3.0 μM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified with single-digit micromolar potency and one with sub-micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize many of the structure–activity relationships observed.