Structure-guided design and photochemical synthesis of new carbamo(dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CLpro.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered a protracted global pandemic from 2019 to 2022, and posed a significant threat to human health. One of the non-structural proteins 3CLpro of SARS-CoV-2 is considered as a validated target for the development of inhibitors against the virus. Disulfiram has been reported as a covalent inhibitor of 3CLpro; however, its structure lacks bonding site with active pockets of 3CLpro and its highly symmetric structure doesn't match well with the irregular cavity of the active center, limiting its therapeutic applications. To enhance their affinity for the 3CLpro target, in this study, two kinds of disulfiram derivatives, designed based on the reevaluation and optimization of disulfiram, have been synthesized through photoredox chemistry, and the novel carbamo(dithioperoxo)thioates 4g-m were found to display 5-17 folds potency against SARS-CoV-2 3CLpro compared to the parent disulfiram, with resulting half-maximal inhibitory concentration (IC50) values ranging from 0.14-0.47 µM. Carbamo(dithioperoxo)thioates 4i containing a 4-hydroxy piperidine and a 4-trifluoromethyl phenyl ring, was identified as the most potent inhibitor to both 3CLpro (IC50 = 0.14 µM) and PLpro (IC50 = 0.04 µM). Furthermore, molecular dynamics simulations, binding free energy analysis and mass analysis were performed and provided insights on the stability, conformational behavior, and interactions of 4g with 3CLpro. The green synthetic methodology, the privileged carbamo(dithioperoxo)thioate scaffold, and the molecular mechanisms presented might serve as a useful system for the further discovery of highly potent inhibitors targeting SARS-CoV-2 3CLpro.

Dearomatization of 3-Aminophenols for Synthesis of Spiro[chromane-3,1'-cyclohexane]-2',4'-dien-6'-ones via Hydride Transfer Strategy-Enabled [5+1] Annulations.

The Sc(OTf)3-catalyzed dearomative [5+1] annulations between readily available 3-aminophenols and O-alkyl ortho-oxybenzaldehydes were developed for synthesis of spiro[chromane-3,1'-cyclohexane]-2',4'-dien-6'-ones. The "two-birds-with-one-stone" strategy was disclosed by the dearomatization of phenols and direct α-C(sp3)-H bond functionalization of oxygen through cascade condensation/[1,5]-hydride transfer/dearomative-cyclization process. In addition, the antifungal activity assay and derivatizations of products were conducted to further enrich the utility of the structure.

Diversity-oriented synthesis of indole-fused scaffolds and bis(indolyl)methane from tosyl-protected tryptamine.

An efficient, diversity-oriented synthesis of indole-1,2-fused 1,4-benzodiazepines, tetrahydro-ß-carbolines, and 2,2'-bis(indolyl)methanes was established starting from tosyl-protected tryptamine. These diverse privileged skeletons were controllably constructed by adjusting different hydride donors and Brønsted acids. A variety of indole-1,2-fused 1,4-benzodiazepines were facilely accessed using benzaldehydes bearing cyclic amines as hydride donors via a cascade N-alkylation/dehydration/[1,5]-hydride transfer/Friedel-Crafts alkylation sequence. The reaction site could be switched when benzaldehydes bearing an alkoxy moiety as hydride donors were used for the generation of tetrahydro-ß-carbolines. On the other hand, the switchable synthesis of 2,2'-bis(indolyl)methanes could be achieved as well by applying p-TsOH·H2O as a catalyst. The reactions feature mild conditions, simple and practical operation, excellent efficiency and the use of EtOH as a green solvent. Using the concept of diversity-oriented, reagent-based synthesis, the inexpensive feedstock tryptamine was efficiently converted to three different types of privileged scaffolds, which facilitates rapid compound library synthesis for accelerating drug discovery.

Controllable Synthesis of N-Heterocycles via Hydride Transfer Strategy-Enabled Formal [5 + 1] and [5 + 2] Cyclizations.

The Brønsted acid-controlled switchable synthesis of indoline-fused tetrahydroquinolines and indole-fused benzazepines was developed through hydride transfer-enabled formal [5 + 1] and [5 + 2] cyclization reactions from indoles and N-alkyl o-aminobenzoketones. Indoline, furanone, and tetrahydroquinoline hybridized pentacyclic products were unprecedentedly accessed via a cascade condensation/hydride transfer/dearomatization-cyclization/deethylation/nucleophilic addition process. In addition, the undeveloped hydride transfer-involved [5 + 2] cyclizations were also realized for direct construction of indole-fused benzazepines.

Controllable Synthesis of N- and O-Containing Heterocycles via Formal [3 + 2] and [5 + 2] Cyclizations.

The controllable synthesis of spirooxindole-dihydrofurans and spirooxindole-benzazepines was developed through formal [3 + 2] and [5 + 2] cyclization reactions from 2-(2-oxoindolin-3-yl)malononitriles and ortho-aminobenzaldehydes, respectively. A variety of spirooxindole-benzazepines were facilely constructed via a furan ring-open-involved hydride transfer/cyclization process. It is noteworthy that the application of the hydride-transfer-involved [5 + 2] cyclization strategy for construction of spirobenzazepines was unprecedented. In addition, the spiro N- and O-containing heterocycles were highly functionalized by amino, amide, and cyano groups, which were conducive to late-stage functionalization.

CRH neurons in the lateral hypothalamic area regulate feeding behavior of mice.

Food cues serve as pivotal triggers for eliciting physiological responses that subsequently influence food consumption. The magnitude of response induced by these cues stands as a critical determinant in the context of obesity risk. Nonetheless, the underlying neural mechanism that underpins how cues associated with edible food potentiate feeding behaviors remains uncertain. In this study, we revealed that corticotropin-releasing hormone (CRH)-expressing neurons in the lateral hypothalamic area played a crucial role in promoting consummatory behaviors in mice, shedding light on this intricate process. By employing an array of diverse assays, we initially established the activation of these neurons during feeding. Manipulations using optogenetic and chemogenetic assays revealed that their activation amplified appetite and promoted feeding behaviors, whereas inhibition decreased them. Additionally, our investigation identified downstream targets, including the ventral tegmental area, and underscored the pivotal involvement of the CRH neuropeptide itself in orchestrating this regulatory network. This research casts a clarifying light on the neural mechanism underlying the augmentation of appetite and the facilitation of feeding behaviors in response to food cues. VIDEO ABSTRACT.

Chemoselective and diastereoselective construction of 4-alkylidene-tetrahydroquinoline via a redox-neutral vinylogous cascade [1,7]-hydride transfer/6-endo-trig cyclization strategy.

Herein, we disclose a chemoselective and diastereoselective synthesis of the medicinally significant 4-alkylidene-tetrahydroquinoline via a redox-neutral vinylogous cascade condensation/[1,7]-hydride transfer/6-endo-trig cyclization strategy, which features a novel product skeleton, high chemoselectivity and diastereoselectivity, facile introduction of 4-alkylidenyl motifs, employment of α,ß,γ,δ-unsaturated dicyanoalkenes as novel hydride acceptors, and green and metal-free conditions with water as the only by-product. Additionally, the versatility of α,α-dicyanoalkenes has been fully exploited as hydride acceptors and γ-exclusive nucleophiles consecutively for accessing novel heterocyclic skeletons.

Alkyl amines and ethers as traceless hydride donors in [1,5]-hydride transfer cascade reactions.

The use of alkyl amines and ethers as traceless hydride donors in [1,5]-hydride transfer cascade reactions represents a promising strategy that greatly enriches redox-neutral hydride transfer chemistry. This review summarizes the remarkable progress made in this field, and focuses on (1) alkyl amines as traceless hydride donors in cascade [1,5]-hydride transfer/elimination reactions and (2) alkyl ethers as traceless hydride donors in [1,5]-hydride transfer cascade reactions. The reaction mechanisms, features, scope, limitations, and synthetic applications are included, where appropriate. Importantly, its powerful ability in allene synthesis and the combination with [Re]-vinylidene and carbocation chemistries render this strategy attractive enough to inspire chemists to develop colorful reactions for building molecular complexity.

[Adsorption Characteristics of Phosphate on Cerium Modified Water Hyacinth Biochar].

A cerium-modified water hyacinth biochar adsorbent(Ce-BC) was developed through co-precipitation-pyrolysis to remove phosphate from wastewater. The study investigated the effects of Ce-BC dosing, wastewater pH, reaction time, and coexisting competing ions on the adsorption process. The results showed that the best adsorption performance was achieved with a maximum adsorption capacity of 35.00 mg·g-1 at a Ce-BC dosage of 0.4 g·L-1 and an initial pH range of 3-10 in the phosphate solution. The adsorption process of phosphate by the Ce-BC followed the quasi-second-order kinetic model, and a phosphate removal efficiency of 98% within 1 h was achieved. In addition, Ce-BC had a strong anti-competitive anion interference and a good regeneration ability; after four cycles of regeneration, the adsorption efficiency remained above 90%. Characterization using field emission scanning electron microscopy-energy dispersive spectrometry(FESEM-EDS), Fourier-transform infrared spectroscopy(FTIR), X-ray diffraction(XRD), and X-ray photoelectron spectroscopy(XPS) showed that the adsorption mechanism of Ce-BC with respect to phosphate mainly involved ligand exchange and inner sphere complexation. The Ce-BC adsorbent prepared in this study effectively removed and recovered phosphates found in domestic sewage, thereby avoiding the eutrophication of water bodies as well as enabling the recovery and utilization of phosphorus resources.

Responses of greenhouse gas emissions to residue returning in China's croplands and influential factors: A meta-analysis.

Climate change is a global issue threatening agricultural production and human survival. However, agriculture sector is a major source of global greenhouse gases (GHGs), especially CH4 and N2O. Crop residue returning (RR) is an efficient practice to sequestrate soil carbon and increase crop yields. However, the efficiency of RR to mitigate climate change and maintain food security will be affected by the response of GHG emissions at both per area-scale and per yield-scale. Therefore, a national meta-analysis was conducted using 309 comparisons from 44 publications to assess the responses of GHG emissions to RR in China's croplands. The results indicated that little response of GWP to RR was observed with conditions under lower nitrogen fertilizer input rates (0-120 kg ha-1), mulch retention, returning one time in double cropping systems, returning with half residue, weakly acidic soil (pH 5.5-6.5), initial SOC contents >20 g kg-1, or mean annual precipitation <1000 mm. In order to mitigate climate change and sustain food security, RR combined with paddy-upland rotation, nitrogen fertilizer input rates of 240-360 kg ha-1, and neutral soil (pH 6.5-7.5) could decrease GWP at per unit of crop yield, which ultimately leads to a lower effect on GHGI and a higher crop production efficiency. In-depth studies should be conducted in the future to explore the interactions between various factors influencing GHG emissions under RR conditions. Overall, optimizing the interactions with management and site-specific conditions, potential for regulating GHGs emissions of RR can be enhanced.

Sex Differences in Electrophysiological Properties of Mouse Medial Preoptic Area Neurons Revealed by In Vitro Whole-cell Recordings.

Despite extensive characterization of sex differences in the medial preoptic area (mPOA) of the hypothalamus, we know surprisingly little about whether or how male and female mPOA neurons differ electrophysiologically, especially in terms of neuronal firing and behavioral pattern generation. In this study, by performing whole-cell patch clamp recordings of the mPOA, we investigated the influences of sex, cell type, and gonadal hormones on the electrophysiological properties of mPOA neurons. Notably, we uncovered significant sex differences in input resistance (male > female) and in the percentage of neurons that displayed post-inhibitory rebound (male > female). Furthermore, we found that the current mediated by the T-type Ca2+ channel (IT), which is known to underlie post-inhibitory rebound, was indeed larger in male mPOA neurons. Thus, we have identified salient electrophysiological properties of mPOA neurons, namely IT and post-inhibitory rebound, that are male-biased and likely contribute to the sexually dimorphic display of behaviors.

Redox-Triggered Switchable Synthesis of 3,4-Dihydroquinolin-2(1H)-one Derivatives via Hydride Transfer/N-Dealkylation/N-Acylation.

The switchable synthesis of 3-non, 3-mono, 3,3'-disubstituted 3,4-dihydroquinolin-2(1H)-ones was developed through a redox-neutral hydride-transfer/N-dealkylation/N-acylation strategy from o-aminobenzaldehyde with 4-hydroxycoumarin, and Meldrum's acid, respectively. The unprecedented strategy for the synthesis of 3,3'-highly functionalized 3,4-dihydroquinolin-2(1H)-one has been realized with the in situ utilization of the released HCHO via the o-QM involved Michael addition. In addition, the synthetic utility of this protocol has been well illustrated via concise synthesis of CYP11B2 inhibitor.

Hydrogen-bonding-assisted redox-neutral construction of tetrahydroquinolines via hydride transfer.

The hydrogen-bonding-assisted construction of tetrahydroquinolines decorated with structurally diverse 3,3'-difunctional groups has been realized via a hydride transfer-involved three-step cascade reaction in the presence of morpholine. This protocol solves the limitation of acyclic 1,3-dicarbonyl compounds by one-pot synthesis of tetrahydroquinolines, featuring operational simplicity, broadly applicable substrates, and metal- and acid-free conditions with EtOH as a hydrogen-bonding donor.

Fluorinated alcohol mediated N,N'-dialkylation of amino acid derivatives via cascade [1,5]-hydride transfer/cyclization for concise synthesis of tetrahydroquinazoline.

Structurally diverse amino acids and their ester derivatives were conveniently N,N'-dialkylated via a TFE-promoted cascade condensation/[1,5]-hydride transfer/cyclization for straightforward construction of pharmeutically significant tetrahydroquinazolines incorporating various amino acids, which featured broad substrate scope, the use of TFE as a sole solvent, additive-free and mild conditions.

Redox-Neutral ß-C(sp3)-H Functionalization of Cyclic Amines via Intermolecular Hydride Transfer.

Herein, we report the first redox-neutral and transition-metal-free ß-C(sp3)-H functionalization of cyclic amines via a consecutive intermolecular hydride transfer process. A series of N-aryl pyrrolidines and N-aryl 1,2,3,4-tetrahydropyridines decorated with CF3 and carboxylic ester functionalities are directly accessed in good yields from pyrrolidines and piperidines. This work pushes forward the application of the intermolecular hydride transfer strategy in one-step assembly of molecular complexity.

Controllable Syntheses of Spiroindolenines and Benzazepinoindoles via Hexafluoroisopropanol-Mediated Redox-Neutral Cascade Process.

The pharmaceutically intriguing spiroindolenines incorporating tetrahydroquinoline were constructed via a hexafluoroisopropanol-promoted redox-neutral cascade cyclization from readily available starting materials. The benzazepinoindole skeletons could also be facilely accessed via one-pot sequential operation. Distinctive features of these transformations include their controllable access of the two privileged skeletons, high efficiency, simple operation, and mild reaction conditions.

Cascade [1,5]-Hydride Transfer/Cyclization for Synthesis of [3,4]-Fused Oxindoles.

The scandium-catalyzed redox-neutral cascade [1,5]-hydride transfer/cyclization between C4-amine-substituted isatins and 1,3-dicarbonyl compounds has been developed. This protocol enabled the synthesis of tricyclic [3,4]-fused oxindoles in good to high yields and excellent diastereoselectivities, featuring high atom- and step economy as well as good functional group tolerance.

Formal [4 + 2] Annulation of Oxindole-Embedded ortho-Quinone Methides with 1,3-Dicarbonyls: Synthesis of Spiro[Chromen-4,3'-Oxindole] Scaffolds.

The oxindole-embedded ortho-quinone methides were employed as reactive intermediates in formal [4 + 2] annulation with 1,3-dicarbonyls, providing an efficient access to spiro[chromen-4,3'-oxindole] scaffolds via a cascade conjugate addition/ketalization/dehydration process. This protocol featured metal-free conditions, wide substrate scope, and excellent yields.

Hydride Transfer Involved Redox-Neutral Cascade Cyclizations for Construction of Spirocyclic Bisoxindoles Featuring a [3,4]-Fused Oxindole Moiety.

The hydride transfer involved redox-neutral cascade cyclization has been developed to construct the spirocyclic bisoxindoles featuring a [3,4]-fused oxindole moiety from rationally designed C4-amine-substituted isatins, affording the diverse tricyclic [3,4]-fused oxindoles with three consecutive chiral centers in good yields and excellent diastereoselectivities (>20:1).