Catalyst Control over S(IV)-stereogenicity via Carbene-derived Sulfinyl Azolium Intermediates.

Stereoselective synthesis utilizing small-molecule catalysts, particularly N-heterocyclic carbene (NHC), has facilitated swift access to enantioenriched molecules through diverse activation modes and NHC-bound reactive intermediates. While carbonyl derivatives, imines, and "activated" alkenes have been extensively investigated, the exploration of heteroatom-centered analogues of NHC-bound intermediates has long been neglected, despite the significant potential for novel chemical transformations they offer once recognized. Herein, we disclose a carbene-catalyzed new activation mode by generating unique sulfinyl azolium intermediates from carbene nucleophilic addition to in situ-generated mixed sulfinic anhydride intermediates. Combined experimental and computational mechanistic investigations pinpoint the chiral NHC-catalyzed formation of sulfinyl azolium intermediate as the enantio-determining step. The novel "S"-based carbene reactive intermediate imparts high efficiency for the catalytic construction of sulfur-stereogenic compounds, giving rise to sulfinate esters with high yields and enantioselectivities under mild conditions. Notably, distinct from most of the NHC-catalyzed enantioselective transformations focusing on the "C" central chiral products, our study realizes a unique carbene-catalyst control over chiral "S" stereocenters via direct asymmetric S-O bond formation for the first time. Furthermore, these sulfinyl-containing products could serve as versatile synthetic platforms for enantioenriched S-stereogenic functional molecules and exhibit remarkable antibacterial activities against rice plant pathogens, which is valuable for the development of novel agrochemical agents.

Carbene-Catalyzed Intermolecular Dehydrogenative Coupling of Aldehydes with C(sp3 )-H Bonds.

The development of catalyst-controlled methods for direct functionalization of two distinct C-H bonds represents an appealing approach for C-C formations in synthetic chemistry. Herein, we describe an organocatalytic approach for straightforward acylation of C(sp3 )-H bonds employing readily available aldehyde as "acyl source" involving dehydrogenative coupling of aldehydes with ether, amine, or benzylic C(sp3 )-H bonds. The developed method affords a broad range of ketones under mild conditions. Mechanistically, simple ortho-cyanoiodobenzene is essential in the oxidative radical N-heterocyclic carbene catalysis to give a ketyl radical and C(sp3 ) radical through a rarely explored intermolecular hydrogen atom transfer pathway, rendering the acylative C-C formations in high efficiency under a metal- and light-free catalytic conditions. Moreover, the prepared products show promising anti-bacterial activities that shall encourage further investigations on novel agrochemical development.

Preparation and cyclodextrin solubilization of the antibacterial agent benzoyl metronidazole.

A one-pot method for the preparation of benzoyl metronidazole was achieved by using N,N'-carbonyldiimidazole as a coupling reagent. Moreover, it was found that the byproduct imidazole as the catalyst promoted the reaction. In addition, the ß-cyclodextrin solubilization of benzoyl metronidazole was investigated by phase-solubility method. The phase-solubility studies indicated that the solubility of benzoyl metronidazole (S = 0.1435 g/L) was substantially increased 9.7-fold (S' = 1.3881 g/L) by formation of 1 : 1 benzoyl metronidazole/ß-cyclodextrin complexes in water, and the association constant K(a) value was determined to be 251 (±23) dm(3)/mol. Therefore, ß-cyclodextrin can work as a pharmaceutical solubilizer for benzoyl metronidazole and may improve its oral bioavailability.

Synthesis and properties of macrocyclic butanoic acid conjugates as a promising delivery formulation for the nutrition of colon.

Butanoic acid plays a significant role in the maintenance of mucosal health and is the preferred energy substrate for the cells in the colon. Here, butanoic acid was selectively conjugated to the secondary hydroxyl group of ß -cyclodextrin through ester bond using sodium hydride as the deprotonation reagent. The preliminary release behaviors of butanoic acid in rat gastrointestinal tract contents were investigated at 37°C within 12 h. In the contents of stomach, the conjugates did seldom release butanoic acid, released butanoic acid only 5.8% in the contents of small intestine, and released butanoic acid significantly up to 38.4% in the contents of colon. These results indicate that the conjugate activation took place site specifically in the rat colonic contents, via the biodegradation by glycosidases and hydrolases in the colon. Therefore, the ß -cyclodextrin conjugates of butanoic acid may be of value as an orally administered colon-specific formulation for the nutrition of colon.

Recent Achievements in Antiviral Agent Development for Plant Protection.

Plant virus disease is the second most prevalent plant diseases and can cause extensive loss in global agricultural economy. Extensive work has been carried out on the development of novel antiplant virus agents for preventing and treating plant virus diseases. In this review, we summarize the achievements of the research and development of new antiviral agents in the recent five years and provide our own perspective on the future development in this highly active research field.

Development of axially chiral urazole scaffolds for antiplant virus applications against potato virus Y.

BACKGROUND: Potato virus Y (PVY) was first discovered by Smith in 1931 and is currently ranked as the fifth most significant plant virus. It can cause severe damage to plants from the family Solanaceae, which results in billions of dollars of economic loss worldwide every year. To discover new antiviral drugs, a class of multifunctional urazole derivatives bearing a stereogenic CN axis were synthesized with excellent optical purities for antiviral evaluations against PVY. RESULTS: The absolute configurations of the axially chiral compounds exhibited obvious distinctions in antiviral bioactivities, with several of these enantio-enriched axially chiral molecules showing excellent anti-PVY activities. In particular, compound (R)-9f exhibited remarkable curative activities against PVY with a 50% maximal effective concentration (EC50 ) of 224.9 µg mL-1 , which was better than that of ningnanmycin (NNM), which had an EC50 of 234.0 µg mL-1 . And the EC50 value of the protective activities of compound (R)-9f was 462.2 µg mL-1 , which was comparable to that of NNM (442.0 µg mL-1 ). The mechanisms of two enantiomer of the axially chiral compounds 9f were studied by both molecule docking and defensive enzyme activity tests. CONCLUSION: Mechanistic studies demonstrated that the axially chiral configurations of the compounds played significant roles in the molecule PVY-CP (PVY Coat Protein) interactions and could enhance the activities of the defense enzymes. The (S)-9f showed only one carbon-hydrogen bond and one π-cation interaction between the chiral molecule and the PVY-CP amino acid sites. In contrast, the (R)-enantiomer of 9f exhibited three hydrogen bonding interactions between the carbonyl groups and the PVY-CP active sites of ARG157 and GLN158. The current study provides significant information on the roles that axial chiralities play in plant protection against viruses, which will facilitate the development of novel green pesticides bearing axial chiralities with excellent optical purities. © 2023 Society of Chemical Industry.

Effects of oxymatrine and matrine on left ventricular contractility using pressure-volume relationship analysis in anesthetized rats.

The purpose of this study was to investigate the effects of oxymatrine and matrine on integrated cardiac function in rats using pressure-volume loop analysis. A pressure-volume loop catheter was advanced into the left ventricle in anesthetized rats. Steady-state hemodynamic and load-independent parameters were recorded before and after oxymatrine or matrine injection. Oxymatrine (200 mg/kg) and matrine (50, 100 mg/kg) significantly increased the preload recruitable stroke work, slope of maximal systolic pressure increase (dP/dtmax) - end-diastolic volume relationship, end-systolic elastance and volume axis intercept (V0), which are load-independent parameters. Furthermore, the observed increased cardiac efficiency, along with the decreased ventricular arterial coupling, pressure volume area and potential energy, reflect improved mechanoenergetics in oxymatrine (200 mg/kg) and matrine (25, 50 or 100 mg/kg) treated rats respectively. In addition, matrine (25, 50 mg/kg) decreased end-systolic volume and end-diastolic volume, and increased ejection fraction; matrine at 100 mg/kg further decreased end-systolic volume, end-diastolic volume, stroke volume and stroke work, shortened the time constant of left ventricular pressure decay, and increased dP/dtmax, and heart rate. These results suggest that both oxymatrine and matrine enhance left ventricular contractility and improve cardiac mechanical function. As the dose of matrine was much lower than that of oxymatrine, the effect of matrine on myocardial contractility was stronger than that of oxymatrine.

Synergistic interaction between matrine and paracetamol in the acetic acid writhing test in mice.

The purpose of this study was to investigate the analgesic interaction between matrine and paracetamol in an acetic acid-induced writhing model in mice. Fifty percent effective dose (ED50) values of the individual drugs were determined, and the different proportions of matrine and paracetamol were assayed using the isobolographic method. Our study demonstrated that both of matrine and paracetamol dose-dependently inhibited the writhing response evoked by acetic acid, and the ED50 values and their 95% confidence intervals against these tonic pain were 21.10 (17.86-24.92) mg/kg and 61.30 (50.71-74.10) mg/kg for matrine and paracetamol, respectively. At the fixed ratios of 1:1, 1:3 and 3:1, the experimental ED50 values of matrine and paracetamol combinations and their 95% confidence intervals were 10.52 (5.14-21.55) mg/kg, 9.13 (4.46-18.70) mg/kg and 4.98 (4.17-5.95) mg/kg, respectively, their theoretical ED50 values and 95% confidence intervals were 41.20 (36.31-46.74) mg/kg, 51.25 (44.19-59.44) mg/kg and 31.15 (27.25-35.60) mg/kg, and the experimental ED50 values of matrine and paracetamol combination were significantly lower than their calculated theoretical ED50 values (all P < 0.01), as revealed by isobolographic analysis. Furthermore, the experimental regression line was also significantly different from the calculated additive equal-effect line over the range of the tested doses (all P < 0.01). Our results suggest that the combination of matrine with paracetamol exerts analgesic synergistic interactions in a mouse acetic acid-induced writhing model, thereby offering a possible therapeutic alternative for the clinical management of inflammatory pain.

Oxymatrine prevents the development of monocrotaline-induced pulmonary hypertension via regulation of the NG, NG-dimethyl-L-arginine metabolism pathways in rats.

The purpose of this study was to investigate the potential effect of oxymatrine in monocrotaline-induced pulmonary hypertension and its possible influence on the NG,NG-dimethyl-L-arginine (ADMA) metabolism pathway. Pulmonary hypertension was induced in rats by a single-dose injection of monocrotaline (60 mg/kg). Daily oral administration of oxymatrine (25, 50 and 100 mg/kg) was started on the day following the monocrotaline injection for 28 days. Oxymatrine (50 and 100 mg/kg) significantly attenuated monocrotaline-induced lung and right ventricular hypertrophy, right ventricular systolic pressure elevation, and right ventricular dysfunction. Oxymatrine also reduced the thickening of monocrotaline-induced pulmonary arterial medial wall. Meanwhile, oxymatrine normalized the level of pulmonary asymmetric ADMA and attenuated the upregulated expression of protein arginine methyltransferase 1 (PRMT1). Oxymatrine had no effect on the expression of protein arginine methyltransferase 2 (PRMT2) and NG,NG-Dimethylarginine dimethylaminohydrolase 1 (DDAH1), which were upregulated in monocrotaline-induced pulmonary arterial hypertensive rats. However, the expression of the protein NG,NG-Dimethylarginine dimethylaminohydrolase 2 (DDAH2) did not differ among all groups (all P﹥0.05). These results suggest that oxymatrine may offer protective effects on the development of pulmonary hypertension by ameliorating pulmonary remodeling and modulating the ADMA metabolism pathway.