Swelling Pores: Porosity is a key parameter when selecting materials for catalysts, chemical separations, gas storage, host-guest interactions, and related chemical processes. In most cases the porosity of a material is fixed. Rabone et al. (p. 1053 ; see the Perspective by Wright ) have described a molecular material in which the size of the pores changed during the sorption process. The porosity increased because a dipeptide linker between metal centers reoriented during uptake of some gases, thus improving the capacity of the material to adsorb.

Formic acid (HCO₂H) is an important potential hydrogen storage material, which, in the presence of appropriate catalysts can be selectively dehydrogenated to give H₂ and CO₂. In this work, well defined N^C cyclometallated iridium(III) complexes based on 2-aryl imidazoline ligands are found to be excellent catalysts for the decomposition of HCO₂H–NEt₃ mixtures to give H₂ and CO₂ under mild conditions with high turnover frequencies (up to 147 000 h⁻¹ at 40 °C) and essentially no CO formation. The modular structures of these catalysts have allowed for the construction of structure–activity relationships for the complexes, leading to the rational optimisation of the catalyst structure with respect to both the rate of H₂ production and catalyst lifetime. In particular, the presence of the remote γ-NH unit in the ligand is shown to be essential for catalytic activity, without which no reaction occurs. Mechanistic studies suggest that the dehydrogenation is rate-limited by the step of hydride protonation, which is made feasible by the γ-NH unit via an unusual form of long-range metal–ligand bifunctional catalysis involving formic acid-assisted proton hopping.

There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase ( Plasmodium falciparum NDH2) and cytochrome bc ₁ . Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites ( Plasmodium cynomolgi ) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria.

Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca’s 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (A∙WOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.