Gigahertz- to terahertz-frequency infrared and Raman spectra contain a wealth of information concerning the structure, intermolecular forces, and dynamics of ionic liquids. However, these spectra generally have a large number of contributions ranging from slow diffusional modes to underdamped librations and intramolecular vibrational modes. This makes it difficult to isolate effects such as the role of Coulombic and hydrogen-bonding interactions. We have applied far-infrared and ultrafast optical Kerr effect spectroscopies on carefully selected ions with a greater or lesser degree of symmetry in order to isolate spectral signals of interest. This has allowed us to demonstrate the presence of longitudinal and transverse optical phonon modes and a great similarity of alkylammonium-based protic ionic liquids to liquid water. The data show that such phonon modes will be present in all ionic liquids, requiring a reinterpretation of their spectra.
PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of different samples of this compound. Herein is described the synthesis of enantiomerically enriched (S)- and (R)-PF74 and further enrichment of the samples (≥98%) using chiral HPLC resolution. The biological activities of each enantiomer were then evaluated, which determined (S)-PF74 (IC50 1.5 µM) to be significantly more active than (R)-PF74 (IC50 19 µM). Computational docking studies were then conducted to rationalise this large discrepancy in activity, which indicated different binding conformations for each enantiomer. The binding energy of the conformation adopted by the more active (S)-PF74 (ΔG = −73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (ΔG = −55.8 kcal/mol) in agreement with experimental observations.
Parasitic nematodes are globally important and place a heavy disease burden on infected humans, crops and livestock, while commonly administered anthelmintics used for treatment are being rendered ineffective by increasing levels of resistance. Although the modes of action and resistance mechanisms caused by detoxification and target site insensitivity for these compounds is well documented, the mechanisms for uptake, which can also cause resistance, are still poorly defined. It has recently been shown in the model nematode Caenorhabditis elegans that the avermectins or macrocyclic lactones such as ivermectin and moxidectin gain entry though the sensory cilia of the amphid neurons. This study interrogated the molecular mechanisms involved in the uptake of avermectins using a combination of forward genetics and targeted resistance screening approaches along with visualising a BODIPY labelled ivermectin analog and confirmed the importance of intraflagellar transport in this process. This approach also identified the protein trafficking pathways used by the downstream effectors and the components of the ciliary basal body that are required for effector entry into these non-motile structures. Mutations in many of the genes under investigation also resulted in resistance to the unrelated anthelmintic drugs albendazole and levamisole, giving insights into the potential mechanisms of multidrug resistance observed in field isolates of the parasitic nematodes that are a scourge of ruminant livestock. In total 50 novel C. elegans anthelmintic survival associated genes were identified in this study, three of which (daf-6, rab-35 and inx-19) are associated with broad spectrum cross resistance. When combined with previously known resistance genes, there are now 53 resistance associated genes which are directly involved in amphid, cilia and IFT function.
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