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Readily available potassium alkynyltrifluoroborates were used for organocatalytic asymmetric conjugate alkynylation of β-enaminones. The interception of a modified binaphthol catalyst and in situ generated organodifluoroboranes proved important to access functionalized β-alkynyl-β-amino carbonyls and derivatives with improved chemo-reactivity and enantio-induction. Mechanistic studies revealed the impact of molecular sieves on efficiency and stereocontrol. The products undergo additional functionalization to yield a diverse set of valuable β-alkynyl-β-amino carbonyl scaffolds.

Mineral resources (such as sulphur, iron, lead, and zinc) are abundant in one of the watersheds in Anhui Province, China. Unfortunately, excessive mining has negatively impacted the surrounding eco...

Enantioselective synthesis of α-amino esters have been achieved through the Petasis borono-Mannich multicomponent reaction using ( R)-BINOL-derived catalysts with stable heteroaryl and alkenyl trifluoroborate salts under mild conditions. The reaction provides direct access to optically active α-amino esters with moderate to good yields and enantioselectivities.

A chiral phosphoric acid-catalyzed kinetic resolution of tertiary allylic alcohols was developed to provide structurally valuable enantioenriched 2,2-disubstituted tetrahydrofurans, tetrahydropyrans, and oxepane. A variety of tertiary allylic alcohols were resolved with selectivity factors of ≤120. A tertiary allylic carbocationic intermediate mediates the enantioselective intramolecular substitution to achieve high regio- and enantioselectivity. A gram-scale reaction with low catalyst loading and subsequent transformations of the recovered alcohols and products demonstrated the utility of this method.

Human neutrophil peptide 1 (HNP1) is a small (3.44 kDa) cationic peptide that is a distinct member of the defensin family. HNP1 plays a crucial role in controlling bacterial infections, particularly by antibiotic-resistant bacteria, through membrane perforation patterns. The structural characteristics of HNP1's three intramolecular disulfide bridges cause difficulty in its synthesis via chemical methods. In this study, bioactive recombinant HNP1 was produced using the Pichia pastoris (P. Pichia) expression system. HNP1 was fused with the polyhedrin of Bombyx mori and enhanced green fluorescent protein (EGFP) to prevent HNP1 toxicity in yeast host cells under direct expression. An enterokinase protease cleavage site (amino acid sequence DDDDK) was designed upstream of the HNP1 peptide to obtain the antibacterial peptide HNP1 with native structure after it was cleaved by the enterokinase. The fusion HNP1 protein (FHNP1) was successfully expressed and had a molecular mass of approximately 62.6 kDa, as determined using SDS-PAGE and Western blot. Then, the recovered FHNP1 was digested and purified; Tricine-SDS-PAGE results showed that HNP1 was successfully released from FHNP1. Functional analysis of induction against antibiotic-resistant Helicobacter pylori (H. pylori) showed that it was challenging for HNP1 to acquire resistance to the antibiotic-resistant H. pylori. Moreover, in vitro studies showed that HNP1 exerted a strong effect against antibiotic-resistant H. pylori activity. Furthermore, the animal model of H. pylori infection established in vivo showed that HNP1 significantly reduced the colonization of antibiotic-resistant H. pylori in the stomach. Our study indicated that this could be a new potential avenue for large-scale production of HNP1 for therapeutic application against the antibiotic-resistant H. pylori infection in humans.

Helicobacter pylori (H. pylori) shows increasingly enhanced resistance to various antibiotics, and its eradication has become a major problem in medicine. The antimicrobial peptide PGLa-AM1 is a short peptide with 22 amino acids and exhibits strong antibacterial activity. In this study, we investigated whether it has anti-H. pylori activity for the further development of anti-H. pylori drugs to replace existing antibiotics. However, the natural antimicrobial peptide PGLa-AM1 shows a low yield and is difficult to separate, limiting its application. A good strategy to solve this problem is to express the antimicrobial peptide PGLa-AM1 using gene engineering at a high level and low cost. For getting PGLa-AM1 with native structure, in this study, a specific protease cleavage site of tobacco etch virus (TEV) was designed before the PGLa-AM1 peptide. For convenience to purify and identify high-efficiency expression PGLa-AM1, the PGLa-AM1 gene was fused with the polyhedrin gene of Bombyx mori (B. mori), and a 6 × His tag was designed to insert before the amino terminus of the fusion protein. The fusion antibacterial peptide PGLa-AM1 (FAMP) gene codon was optimized, and the gene was synthesized and cloned into the Escherichia coli (E. coli) pET-30a (+) expression vector. The results showed that the FAMP was successfully expressed in E. coli. Its molecular weight was approximately 34 kDa, and its expression level was approximately 30 mg/L. After the FAMP was purified, it was further digested with TEV protease. The acquired recombinant antimicrobial peptide PGLa-AM1 exerted strong anti-H. pylori activity and therapeutic effect in vitro and in vivo.

(+)- and (−)-Lesinurad were isolated as atropisomers from racemic lesinurad for the first time. No interconversion was observed between the two atropisomers under various conditions tested. The two atropisomers showed significant differences in hURAT1 highly expressed HEK293 cell-based inhibition assays, monkey pharmacokinetic studies, and in vitro human recombinant CYP2C9 stability studies. It was speculated that (+)-lesinurad might offer a better hyperuricemia/gout therapy than (−)-lesinurad or the racemate.

Amphihevir, a benzofuran derivative, is the first reported hepatitis C virus (HCV) nonstructural protein 4B (NS4B) inhibitor that has advanced to clinical trials (currently in phase Ib trial [CTR20170632]). Here, we report the results of a preclinical study of its potency, toxicity, selectivity, drug metabolism and pharmacokinetics (DMPK), and safety profiles. Amphihevir displayed good antiviral activities against genotype 1a (50% effective concentration [EC(50)] of 0.34 nM) and genotype 1b (EC(50) of 1.97 nM) replicons and no cytotoxicity in 12 cell lines derived from animals and humans. Amphihevir was found to be inactive against other viruses, human kinases, and G protein-coupled receptors (GPCRs), which implies its good selectivity. A 9-day long-term treatment of genotype 1b replicons with amphihevir resulted in a 3.8 Log(10) decline of the hepatitis C viral RNA at a concentration of 25× EC(90). Drug resistance screening showed that mutations occurred at H94, F98, and V105 of NS4B, which mediated the resistance to amphihevir. This result suggests that NS4B is the main target of amphihevir. There was no cross-resistance between amphihevir and NS5A, NS3/4A, and NS5B inhibitors, suggesting that amphihevir in combination with other anti-hepatitis C virus drugs could be used to treat hepatitis C, as proven by studies of amphihevir and other hepatitis C virus inhibitors. Pharmacokinetic studies demonstrated that amphihevir has good oral bioavailability and appropriate half-life (t(1/2)) in rats and dogs, thereby supporting its use once per day. Finally, amphihevir showed good safety profiles in rats and dogs. The results shed light on the use of amphihevir as a potential treatment option for chronic hepatitis C patients.

The aim of this study was to probe the potential anti-H. pylori activity of the synthetic antimicrobial peptide pexiganan, which is an analog of the peptide magainin, and its nanoparticles (PNPs) that were prepared in our laboratory. To compare their antibacterial effects in vitro and in vivo, studies of H. pylori growth inhibition, kinetics and resistance assays were undertaken. The gastric mucoadhesive efficiency and H. pylori clearance efficiency of pexiganan and PNPs were evaluated in rats and mice infected with H. pylori. The eradication of H. pylori was determined using urease tests and a microbial culture method. We observed that PNPs adhered to gastric mucosa more effectively owing to a prolonged stay in the stomach, which resulted in a more effective H. pylori clearance. In addition, PNPs had greater anti-H. pylori effect than pexiganan in infected mice. The amount of pexiganan required to eradicate H. pylori was significantly less using PNPs than the corresponding pexiganan suspension. The results confirmed that PNPs improved peptide stability in the stomach and more effectively eradicated H. pylori from mice stomachs than pexiganan.

Metronidazole (MNZ) is an effective agent that has been employed to eradicate Helicobacter pylori (H. pylori). The emergence of broad MNZ resistance in H. pylori has affected the efficacy of this therapeutic agent. The concentration of MNZ, especially the mutant prevention concentration (MPC), plays an important role in selecting or enriching resistant mutants and regulating therapeutic effects. A strategy to reduce the MPC that can not only effectively treat H. pylori but also prevent resistance mutations is needed. H. pylori is highly resistant to lysozyme. Lysozyme possesses a hydrolytic bacterial cell wall peptidoglycan and a cationic dependent mode. These effects can increase the permeability of bacterial cells and promote antibiotic absorption into bacterial cells. In this study, human lysozyme (hLYS) was used to probe its effects on the integrity of the H. pylori outer and inner membranes using as fluorescent probe hydrophobic 1-N-phenyl-naphthylamine (NPN) and the release of aspartate aminotransferase. Further studies using a propidium iodide staining method assessed whether hLYS could increase cell permeability and promote cell absorption. Finally, we determined the effects of hLYS on the bactericidal dynamics and MPC of MNZ in H. pylori. Our findings indicate that hLYS could dramatically increase cell permeability, reduce the MPC of MNZ for H. pylori, and enhance its bactericidal dynamic activity, demonstrating that hLYS could reduce the probability of MNZ inducing resistance mutations.

Helicobacter pylori (H. pylori)-induced oxidative stress has been shown to play a very important role in the inflammation of the gastric mucosa and increases the risk of developing gastric cancer. Resveratrol has many biological functions and activities, including antioxidant and anti-inflammatory effect. The purpose of this study was to probe whether resveratrol inhibits H. pylori-induced gastric inflammation and to elucidate the underlying mechanisms of any effect in mice. A mouse model of H. pylori infection was established via oral inoculation with H. pylori. After one week, mice were administered resveratrol (100 mg/kg body weight/day) orally for six weeks. The mRNA and protein levels of iNOS and IL-8 were assessed using RT-PCR, Western blot and ELISA. The expression levels of IκBα and phosphorylated IκBα (which embodies the level and activation of NF-κB), Heme Oxygenase-1 (HO-1, a potent antioxidant enzyme) and nuclear factor-erythroid 2 related factor 2 (Nrf2) were determined using Western blot, and lipid peroxide (LPO) level and myeloperoxidase (MPO) activity were examined using an MPO colorimetric activity assay, thiobarbituric acid reaction, and histological-grade using HE staining of the gastric mucosa. The results showed that resveratrol improved the histological infiltration score and decreased LPO level and MPO activity in the gastric mucosa. Resveratrol down-regulated the H. pylori-induced mRNA transcription and protein expression levels of IL-8 and iNOS, suppressed H. pylori-induced phosphorylation of IκBα, and increased the levels of HO-1 and Nrf2. In conclusion, resveratrol treatment exerted significant effects against oxidative stress and inflammation in H. pylori-infected mucosa through the suppression of IL-8, iNOS, and NF-κB, and moreover through the activation of the Nrf2/HO-1 pathway.