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Antibiotics are essential for treating infections and reducing risks during medical interventions. However, many commonly used antibiotics lack the physiochemical properties for an efficient oral administration when treating systemic infection. Instead, we are reliant on intravenous delivery, which presents complications outside of clinical settings. Developing novel formulations for oral administration is a potential solution to this problem. We engineered hexosome and cubosome liquid crystal nanoparticles (LCNPs) characterized by small-angle X-ray scattering and cryogenic transmission electron microscopy, and could encapsulate the antibiotics vancomycin (VAN) and clarithromycin (CLA) with high loading efficiencies. By rationally choosing stable lipid building blocks, the loaded LCNPs demonstrated excellent resilience against enzymatic degradation in an in vitro gut model LCNP stability is crucial as premature antibiotic leakage can negatively impact the gut microbiota. In screens against the representative gut bacteria Enterococcus faecalis and Escherichia coli, our LCNPs provided a protective effect. Furthermore, we explored co-administration and dual loading strategies of VAN and CLA, and demonstrated effective loading, stability and protection for E. faecalis and E. coli. This work represents a proof of concept for the early-stage development of antibiotic-loaded LCNPs to treat systemic infection via oral administration, opening opportunities for combination antibiotic therapies.

In this study, we present the synthesis and analysis of a novel, air-stable, and solvent-resistant phosphaalkene switch. Using this symmetric switch, we have demonstrated degenerate photoisomerization experimentally for the first time. With a combination of photochemical-exchange NMR spectroscopy, ultrafast transient absorption spectroscopy, and quantum chemical calculations, we elucidate the isomerization mechanism of this symmetric phosphaalkene, comparing it to two other known molecules belonging to this class. Our findings highlight the critical role of the isolobal analogy between C=P and C=C bonds in governing nanoscale molecular motion and break new ground for our understanding of light-induced molecular processes in symmetric heteroalkene systems.

The 3-chymotrypsin-like protease (3CL^pro) is a crucial enzyme for the replication of coronaviruses, notable for its high conservation across viral species and the lack of human analogs. These characteristics make it a prime target for the development of broad-spectrum antiviral medications. In this work, we incorporated the zolinium as a hydrophilic group and a ketone as the covalent warhead to develop novel agents targeting SARS-CoV-2 3CL^pro. We designed and synthesized 60 derivatives to systematically study their structure-activity relationships (SAR). Of these, compound 46 demonstrated the most potent inhibition against 3CL^pro (IC₅₀ = 1.75 ± 0.039 μM) and good selectivity against other five enzymes, with reasonable chemical stability and rapid reactivity with cysteine. Mass spectrometry-based peptide mapping revealed that the ketone group of compound 46 covalently modified Cys44 of SARS-CoV-2 3CL^pro. The inactivation kinetics indicated that compound 46 reduced the 3CL^pro activity in a time- and dose-dependent manner, with an inactivation efficiency constant (k_inact/K_i) of 0.011 min^-1μM^-1. Further covalent docking and molecular dynamics simulations elucidated the binding mechanism involving the disruption of protein's dimer interface and stability, which was partially validated by Native-PAGE analysis. Moreover, compound 46 exhibited negligible cytotoxicity and good metabolic stability in liver microsome assays, positioning it as a promising covalent lead for the advancement of broad-spectrum anti-coronavirus therapies.

Three new dihydroflavonols, gloverinols A–C (1–3), a new flavon-3-ol, gloverinol D (4), two new isoflavans, gloveriflavan A (5) and B (6), and seven known compounds were isolated from the root bark of Dalbergia gloveri. The structures of the isolates were elucidated by using NMR, ECD, and HRESIMS data analyses. Among the isolated compounds, gloverinol B (2), gloveriflavan B (6), and 1-(2,4-dihydroxyphenyl)-3-hydroxy-3-(4-hydroxyphenyl)-1-propanone (10) were the most active against Staphylococcus aureus, with MIC values of 9.2, 18.4, and 14.2 μM, respectively.

An A129G/R134V/S166G triple mutant of fructose 6-phosphate aldolase (FSA) from Escherichia coli was further engineered with the goal to generate new enzyme variants capable of catalyzing aldol reactions between aryl substituted ketones and aldehydes. Residues L107 and L163 were subjected to saturation mutagenesis and the resulting library of FSA variants was screened for catalytic activity with 2-hydroxyacetophenone and phenylacetaldehyde as substrates. A selection of aldolase variants was identified that catalyze the synthesis of 2,3-dihydroxy-1,4-diphenylbutanone. The most active enzyme variants contained an L163C substitution. An L107C/L163C variant was further tested for activity with substituted phenylacetaldehydes, and was shown to afford the production of the corresponding diphenyl substituted butanones with good diastereoselectivities (anti : syn dr of 10 to 30) and reasonable to good enantioselectivities of syn enantiomers (er of 5 to 25).

Three new compounds, the silphiperfolanol angelate ester umutagarananol (1), the macrocyclic pyrrolizidine alkaloids umutagarinine A and B (2–3), and five known secondary metabolites (4–8) were isolated from the CH₂Cl₂−MeOH (1 : 1) extract of the roots and the stem bark of Solanecio mannii (Hook. f.) (Asteraceae). The isolated compounds were characterized by NMR and IR spectroscopic, and mass spectrometric analyses, whereas the relative stereochemistry of 4 was established by NAMFIS-based combined computational and solution NMR analysis. Synthetic modification of 5 provided two new compounds, 2-angeloyloxy-4,8-epoxypresilphiperfolane (9) and 2-angeloyloxy-4,8-epoxypresilphi-perfolane (10). The crude extracts and the isolated constituents showed weak antibacterial activities (EC₅₀ 0.7–13.3 mM) against the Gram-negative Escherichia coli and the Gram-positive Bacillus subtilis. Compounds 2, 3 and 4 exhibited strong cytotoxicity against MCF-7 human breast cancer cells, with EC₅₀ values of 35.6, 21.7 and 12.5 μM, respectively.

Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide. Molecular dynamics using an explicit solvent model, but not the Monte Carlo method with implicit solvation, handled both solvents correctly. Refinement of conformations at the ab initio level was fundamental to reproducing the experimental observations-standard state-of-the-art molecular mechanics force fields were insufficient. Our simulations correctly predicted the intramolecular interactions between side chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic ring. Our results provide a platform for the rational, prospective design of molecular chameleons that adapt to the properties of the environment.

The acidic demetallation of a series of sparsely substituted Zn(II) chlorins is reported. The chlorins were functionalized in the 10-position with substituents ranging from strongly electron donating mesityl and p-methoxyphenyl to electron-withdrawingp-nitrophenyl and pentafluorophenyl groups. The demetallation kinetics were investigated using UV-Visible absorption spectroscopy. Demetallation was carried out by exposing the metallochlorins dissolved in CH2Cl2 to an excess of trifiuoroacetic acid. Reasonable correlation was found between the Hammett constant of the 10-substituent and the rate constant of the loss of the metal ion. The largest differences were observed between the p-methoxyphenyl and p-nitrophenyl-substituted Zn(II) chlorins, undergoing loss of Zn(II) with pseudo first order rate constants of 0.0789 x 10(-3) and 3.70 x 10(-3) min(-1), respectively. Taken together, these data establish the dramatic influence even subtle changes can have in altering the electronic properties of chlorins, which in turn impacts metallochlorin function.

Unlike N-confused porphyrins which are well-known and extensively studied tetrapyrroles, N-confused hydroporphyrins are almost unknown, largely because so far they have resisted attempts at rational synthesis. Here, we report our efforts towards the total synthesis of N-confused hydroporphyrins. We have prepared N-confused building blocks analogous to the non-N-confused substrates in the Lindsey synthesis of sparsely substituted chlorins. We have systematically flipped the A, B and C pyrrole rings in the dipyrrolic precursors of the target N-confused macrocycles, preparing in total an N-confused "Western half' (tetrahydrodipyrrin) and two N-confused "Eastern halves" (brominated formyldipyrromethanes). These were subjected to a range of cyclization conditions. While we successfully isolated and identified three macrocyclic products, none of these proved to be the desired N-confused hydroporphyrin.

Multiplex imaging in the red and near-infrared (NIR) should be an enabling tool for the real-time investigation of biological systems. Currently available emitters have short luminescent lifetimes, broad absorption and emission bands, and small Stokes shifts, which limits multiplexing in this region to two colors. NIR-emitting luminescent lanthanide (Ln) complexes carrying hydroporphyrin (chlorin) sensitizing antennae are excitable in the red through the narrow, intense and tunable chlorin absorptions. Both emission- and excitation-based multiplexing are possible, the former by exciting the same antenna appended to different Lns, the latter by attaching different chlorins with nonoverlapping absorptions to the same Ln. The combination of excitation and emission spectroscopies allows for the straightforward differentiation of up to four different complexes.