Preparation of Indolin-3-one-Containing 1,4-Naphthoquinone Derivatives via Organocatalytic Asymmetric Michael Addition Reaction.

This article explores the asymmetric Michael addition reaction of 2-hydroxy-1,4-naphthoquinone and indole-3-ones catalyzed by cinchona alkaloids. This strategy utilizes 2-hydroxy-1,4-naphthoquinone and easily prepared indole-3-one as substrates, resulting in the synthesis of 23 unprecedented indolin-3-ones bearing a 1,4-naphthoquinone unit at the C2 position of indole under simple and mild reaction conditions, with up to 88% yield, 98% ee, and >20:1 dr.

Rh(III)-Catalyzed C7-Alkylation of Isatogens with Malonic Acid Diazoesters.

Rh(III)-catalyzed C7-alkylation of isatogens (indolin-3-one N-oxides) with malonic acid diazoesters has been developed. This strategy utilizes oxygen anion on the N-oxide group of isatogens as a directing group and successfully achieves the synthesis of a series of C7-alkylated isatogens with moderate to good yields (48-86% yields). Moreover, the N-oxides of isatogens can not only serve as the simple directing group for C7-H bond cleavage but also be deoxidized for easy removal.

Protecting-Group-Free Synthesis of Meridianin A-G and Derivatives and Its Antibiofilm Evaluation.

Herein, a protecting-group-free protocol was developed to realize a time and step economy diversification of the Meridianin alkaloid. A broad range of substituents are tolerated to deliver the products in moderate to high yields, and the first synthesis of Meridianin B was achieved. The simplicity of this protocol enables the rapid construction of a Meridianin derivative library for antibiofilm evaluation. Preliminary results reveal that Meridianin derivatives were capable of inhibiting the Acinetobacter baumannii biofilm and lowering the antibiotic MIC synergistically.

Design, synthesis and biological evaluation of new multi-target scutellarein hybrids for treatment of Alzheimer's disease.

Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a-i, containing a 2-hydroxymethyl-3,5,6-trimethylpyrazine fragment at the 7-position of scutellarein, were found to have balanced and effective multi-target potencies against AD. Among them, compound 11e exhibited the most potent inhibition of electric eel and human acetylcholinesterase enzymes with IC50 values of 6.72 ± 0.09 and 8.91 ± 0.08 µM, respectively. In addition, compound 11e displayed not only excellent inhibition of self- and Cu2+-induced Aß1-42 aggregation (91.85% and 85.62%, respectively) but also induced disassembly of self- and Cu2+-induced Aß fibrils (84.54% and 83.49% disaggregation, respectively). Moreover, 11e significantly reduced tau protein hyperphosphorylation induced by Aß25-35, and also exhibited good inhibition of platelet aggregation. A neuroprotective assay demonstrated that pre-treatment of PC12 cells with 11e significantly decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins (Bcl-2, Bax and caspase-3) and inhibited RSL3-induced PC12 cell ferroptosis. Furthermore, hCMEC/D3 and hPepT1-MDCK cell line permeability assays indicated that 11e would have optimal blood-brain barrier and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11e significantly attenuated learning and memory impairment in an AD mice model. Toxicity experiments with the compound did not reveal any safety concerns. Notably, 11e significantly reduced ß-amyloid precursor protein (APP) and ß-site APP cleaving enzyme-1 (BACE-1) protein expression in brain tissue of scopolamine-treated mice. Taken together, these outstanding properties qualified compound 11e as a promising multi-target candidate for AD therapy, worthy of further studies.

The Discovery of Indole-2-carboxylic Acid Derivatives as Novel HIV-1 Integrase Strand Transfer Inhibitors.

As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 µM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

DBU-Catalyzed Aerobic CDC Reaction of Thiophenols.

A convenient method was developed for the preparation of thiolated compounds via a DBU-catalyzed aerobic cross-dehydrogenative coupling (CDC) reaction. The established protocol is environmentally friendly and operationally simple. Substrates like (hetero)aryl acetates, (hetero)aryl ketones, and indoles could be transformed into the corresponding thiolated products in moderate to high yields and further applied in the preparation of bioactive compounds in a prefunctionalization-free manner.

Synthesis and antibiofilm evaluation of N-acyl-2-aminopyrimidine derivatives against Acinetobacter baumannii.

The overuse of antibiotics will led to the increase of drug resistance. Especially, the multidrug-resistant A. baumannii became the leading cause of nosocomial infections with high rates of morbimortality. The drug resistance of A. baumannii is greatly attributed to its biofilm. To alleviate the burden of drug resistance, the anti-virulence signaling strategies was developed. By specifically interfering with the ability of the bacteria to recognize host signals that are needed to establish infection, the bacteria are less able to colonize the host. In this paper, 39 N-acyl-2-aminopyrimidine derivatives were synthesized and tested for their biofilm inhibition efficacy. The screening results reveal that some of the analogues (3ac, 8d) efficiently inhibited the biofilm formation of A. baumannii (IC50 as low as 3.8 µM), and the biofilm inhibition ability was further demonstrated with laser confocal results and extracellular polysaccharides inhibition test. Further motility test reveals our compounds are quorum sensing inhibitors. Besides, the synergistic effect of compounds 3ac and 8d with different antibiotics suggest its potential clinical significance, which was further enhanced by the long time biofilm inhibition test after coating with PLGA. Finally, we also look into the safety of the compounds with cytotoxicity assay.

Design, synthesis and evaluation of novel scutellarin and scutellarein-N,N-bis-substituted carbamate-l-amino acid derivatives as potential multifunctional therapeutics for Alzheimer's disease.

In this study, we designed, synthesized and evaluated a series of scutellarin and scutellarein-N,N-bis-substituted carbamate-l-amino acid derivatives as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds containing scutellarein as the parent nucleus (6a-l) had good inhibitory activity against acetyl cholinesterase (AChE), with compound 6 h exhibiting the most potent inhibition of electric eel AChE and human AChE enzymes with IC50 values of 6.01 ± 1.66 and 7.91 ± 0.49 µM, respectively. In addition, compound 6 h displayed not only excellent inhibition of self- and Cu2+-induced Aß1-42 aggregation (89.17% and 86.19% inhibition) but also induced disassembly of self- and Cu2+-induced Aß fibrils (84.25% and 78.73% disaggregation). Moreover, a neuroprotective assay demonstrated that pre-treatment of PC12 cells with 6 h significantly decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins (Bcl-2, Bax, and caspase-3) and inhibited RSL3 induced PC12 cell ferroptosis. Furthermore, hCMEC/D3 and hPepT1-MDCK cell line permeability assays indicated that 6 h would have optimal blood-brain barrier and intestinal absorption characteristics. The in vivo experimental data suggested that 6 h ameliorated learning and memory impairment in mice by decreasing AChE activity, increasing ACh levels and alleviating pathological damage of hippocampal tissue cells. These multifunctional properties highlight compound 6 h as a promising candidate for development as a multifunctional drug against AD.

Role of no table salt on hypertension and stroke based on large sample size from National Health and Nutrition Examination Survey database.

BACKGROUND: To assess the associations between no table salt and hypertension or stroke. METHODS: The data of 15,352 subjects were collected from National Health and Nutrition Examination Survey (NHANES) database. All subjects were divided into no hypertension or stroke group (n = 10,894), hypertension group (n = 5888), stroke group (n = 164) and hypertension and stroke group (n = 511). Univariate and multivariate logistic regression analysis was used to measure the associations of salt type used with hypertension and stroke and co-variables were respectively adjusted in different models. RESULTS: After adjusting age and gender, other salt intake was associated with 1.88-fold risk of hypertension (OR = 1.88, 95%CI: 1.44-2.46) and no table salt was associated with 1.30-fold risk of hypertension (OR = 1.30, 95%CI: 1.15-1.47). After adjusting age, gender, race, BMI, PIR, marital status, CVDs, whether doctors' told them to reduce salt, and diabetes, the risk of hypertension was 1.23-fold increase in no table salt group (OR = 1.23, 95%CI: 1.04-1.46). After the adjustment of age and gender, the risk of hypertension and stroke was 3.33-fold increase (OR = 3.33, 95%CI: 2.12-5.32) in other salt intake group and 1.43-fold increase (OR = 1.43, 95%CI:1.17-1.74) in no table salt group. CONCLUSION: Other salt intake or no table salt were associated with a higher risk of hypertension or hypertension and stroke.

Transcriptome Analysis of Tryptophan-Induced Resistance against Potato Common Scab.

Potato common scab (CS) is a worldwide soil-borne disease that severely reduces tuber quality and market value. We observed that foliar application of tryptophan (Trp) could induce resistance against CS. However, the mechanism of Trp as an inducer to trigger host immune responses is still unclear. To facilitate dissecting the molecular mechanisms, the transcriptome of foliar application of Trp and water (control, C) was compared under Streptomyces scabies (S) inoculation and uninoculation. Results showed that 4867 differentially expressed genes (DEGs) were identified under S. scabies uninoculation (C-vs-Trp) and 2069 DEGs were identified under S. scabies inoculation (S-vs-S+Trp). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that Trp induced resistance related to the metabolic process, response to stimulus, and biological regulation. As phytohormone metabolic pathways related to inducing resistance, the expression patterns of candidate genes involved in salicylic acid (SA) and jasmonic acid/ethylene (JA/ET) pathways were analyzed using qRT-PCR. Their expression patterns showed that the systemic acquired resistance (SAR) and induced systemic resistance (ISR) pathways could be co-induced by Trp under S. scabies uninoculation. However, the SAR pathway was induced by Trp under S. scabies inoculation. This study will provide insights into Trp-induced resistance mechanisms of potato for controlling CS, and extend the application methods of Trp as a plant resistance inducer in a way that is cheap, safe, and environmentally friendly.

Design, Synthesis, and Biological Evaluation of N14-Amino Acid-Substituted Tetrandrine Derivatives as Potential Antitumor Agents against Human Colorectal Cancer.

As a typical dibenzylisoquinoline alkaloid, tetrandrine (TET) is clinically used for the treatment of silicosis, inflammatory pulmonary, and cardiovascular diseases in China. Recent investigations have demonstrated the outstanding anticancer activity of this structure, but its poor aqueous solubility severely restricts its further development. Herein, a series of its 14-N-amino acid-substituted derivatives with improved anticancer effects and aqueous solubility were designed and synthesized. Among them, compound 16 displayed the best antiproliferative activity against human colorectal cancer (HCT-15) cells, with an IC50 value of 0.57 µM. Compared with TET, 16 was markedly improved in terms of aqueous solubility (by 5-fold). Compound 16 significantly suppressed the colony formation, migration, and invasion of HCT-15 cells in a concentration-dependent manner, with it being more potent in this respect than TET. Additionally, compound 16 markedly impaired the morphology and motility of HCT-15 cells and induced the death of colorectal cancer cells in double-staining and flow cytometry assays. Western blot results revealed that 16 could induce the autophagy of HCT-15 cells by significantly decreasing the content of p62/SQSTM1 and enhancing the Beclin-1 level and the ratio of LC3-II to LC3-I. Further study showed that 16 effectively inhibited the proliferation, migration, and tube formation of umbilical vein endothelial cells, manifesting in a potent anti-angiogenesis effect. Overall, these results revealed the potential of 16 as a promising candidate for further preclinical studies.

iTRAQ-Based Proteomics Analysis of Response to Solanum tuberosum Leaves Treated with the Plant Phytotoxin Thaxtomin A.

Thaxtomin A (TA) is a phytotoxin secreted by Streptomyces scabies that causes common scab in potatoes. However, the mechanism of potato proteomic changes in response to TA is barely known. In this study, the proteomic changes in potato leaves treated with TA were determined using the Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) technique. A total of 693 proteins were considered as differentially expressed proteins (DEPs) following a comparison of leaves treated with TA and sterile water (as a control). Among the identified DEPs, 460 and 233 were upregulated and downregulated, respectively. Based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, many DEPs were found to be involved in defense and stress responses. Most DEPs were grouped in carbohydrate metabolism, amino acid metabolism, energy metabolism, and secondary metabolism including oxidation-reduction process, response to stress, plant-pathogen interaction, and plant hormone signal transduction. In this study, we analyzed the changes in proteins to elucidate the mechanism of potato response to TA, and we provided a molecular basis to further study the interaction between plant and TA. These results also offer the option for potato breeding through analysis of the resistant common scab.

Unexpected small molecules as novel SIRT2 suicide inhibitors.

A series of sirtuin inhibitor candidates were assembled based on an intermediate ester (1a) our accidently discovered. After screening and evaluation, several SIRT2 selective inhibitors were identified, which can inhibit all the deacetylation, defatty-acylation and debenzoylation of SIRT2. Among these inhibitors, compound 1e was the best SIRT2 selective inhibitors. The primary study on the inhibitory mechanism indicated that compound 1e may be a suicide inhibitor acting as an irreversible way. Given almost all reported sirtuin inhibitors are non-covalent, sirtuin covalent inhibitors are still need to be developed. These findings will facilitate for further development of SIRT2 selective and suicide inhibitors.

Discovery of tetrandrine derivatives as tumor migration, invasion and angiogenesis inhibitors.

Metastatic progression of cancer is a complex and clinically daunting process, with migration, invasion and angiogenesis being the key features. Tetrandrine (TET) is a typical dibenzylisoquinoline alkaloid with promising anti-tumor activity. In our previous work, a number of TET derivatives were designed and synthesized with obvious anti-proliferation activities against cancer cells, however, the anti-metastatic effects of these compounds were not evaluated. In the current investigation, five TET derivatives (8, 18, 32, 71, and 72) with pronounced anti-proliferative activities (IC50 values of 1.00, 1.91, 3.43, 3.78, and 1.93 µM, respectively) against human umbilical vein endothelial cells (HUVECs) were screened out. Scratch assays showed that these compounds significantly suppressed the migration of HUVECs and induced their apoptosis. Among them, derivatives 8 and 72 obviously inhibited the proliferation, colony formation and invasion of HCT-15 cells. Tube formation assays revealed that 4 µM of 8 or 72 remarkably inhibited the tube forming capacity of HUVECs. Moreover, 8 and 72 surpressed the formation of filopodia in HUVECs and severely impaired their motility. Both compounds effectively inhibited the angiogenesis in the zebrafish model with low toxicities in vivo. These results indicated that TET derivatives 8 and 72 are promising anti-metastatic inhibitors.

A Series of Novel HDAC Inhibitors with Anthraquinone as a Cap Group.

Although anthraquinone derivatives possess significant antitumor activity, most of them also displayed those side effects like cardiotoxicity, mainly owing to their inhibition of topoisomerase II of DNA repair mechanisms. Our raised design strategy by switching therapeutic target from topoisomerase II to histone deacetylase (HDAC) has been applied to the design of anthraquinone derivatives in current study. Consequently, a series of novel HDAC inhibitors with a tricylic diketone of anthraquinone as a cap group have been synthesized. After screening and evaluation, compounds 4b, 4d, 7b and 7d have displayed the comparable inhibition in enzymatic activity and cell proliferation than that of Vorinostat (SAHA). Notably, compound 4b showed certain selectivity of antiproliferative effects on cancer cell lines over non-cancer cell lines.

Reductant-Free Aerobic Hydroxylation of Isoquinoline-1,3(2 H,4 H)-dione Derivatives.

Base-catalyzed efficient hydroxylation of isoquinoline-1,3(2 H,4 H)-diones with air under transition-metal-free and reductant-free conditions was established. This methodology is essentially mild and compatible with a broad range of substrates, including aryl, heteroaryl, and alkyl groups. Also, the product could be simply transformed into a hydroxylated tetrahydroisoquinoline core structure through a reductive process.

Organocatalytic Asymmetric α-Sulfenylation of 2-Substituted Indolin-3-ones: A Strategy for the Synthesis of Chiral 2,2-Disubstituted Indole-3-ones with S- and N-Containing Heteroquaternary Carbon Stereocenter.

An organocatalytic asymmetric α-sulfenylation of 2-substituted indolin-3-ones with N-(alkylthio or arylthio)succinimides has been developed for the first time using Cinchona-derived squaramide as the catalyst. Various chiral 2,2-disubstituted indole-3-ones with S- and N-containing heteroquaternary carbon stereocenters were obtained with up to 98% yield and 99% ee.

Hybrid molecules of scutellarein and tertramethylpyrazine's active metabolites for ischemic stroke.

A series of hybrid molecules of scutellarein and tertramethylpyrazine's active metabolites have been synthesized. Compared to the original compound, these prepared compounds exhibited higher water solubility, more appropriate logP and better stability. Importantly, compounds 11b, 11d and 11e showed improved neuroprotective activity against the H2O2-induced cell death in PC12 cells, and better antithrombosis activity. The optimized compound 11b was further evaluated by cerebral ischemia/ reperfusion in the middle cerebral artery occlusion (MCAO) model, the results showed that the compound could significantly reduce the infarct area and decrease the neuronal cell damage in CA1 pyramidal neurons. Overall, we demonstrated that the twin drug strategy could be applied in the development of agents for the treatment of ischemic stroke.

Design, synthesis, and biological evaluation of 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide derivatives as potent HIV-1 Vif inhibitors.

Viral infectivity factor (Vif) is one of the accessory protein of human immunodeficiency virus type I (HIV-1) that inhibits host defense factor, APOBEC3G (A3G), mediated viral cDNA hypermutations. Previous work developed a novel Vif inhibitor 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide (1) with strong antiviral activity. Through optimizations on the two side branches, a series of compound 1 derivatives (2-18) were designed, synthesized and tested in vitro for their antiviral activities. The biological results showed that compound 5 and 16 inhibited the virus replication efficiently with EC50 values of 9.81 and 4.62 µM. Meanwhile, low cytotoxicities on H9 cells were observed for the generated compounds by the MTT assay. The structure-activity relationship of compound 1 was preliminarily clarified, which gave rise to the development of more potent Vif inhibitors.

Synthesis, pharmacological evaluation, and mechanistic study of adefovir mixed phosphonate derivatives bearing cholic acid and l-amino acid moieties for the treatment of HBV.

The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono l-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na+-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 6c as the optimal molecular candidate, with the highest antiviral activity (EC50 0.42 µmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 6c exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 6c cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 6c indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and l-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 6c is a potential candidate as an anti-HBV therapy and therefore merits further investigation.