•Novel 9,13-disubstituted berberine derivatives were synthesized and evaluated for the antistaphylococcal activity.•The antibacterial activities were investigated against several Staphylococcus aureus strains.•Most berberine derivatives (16–35) exhibited better antibacterial activity than berberine.•Compound 20 showed the most potent antibacterial activity.A series of novel 9, 13-disubstituted berberine derivatives have been synthesized and evaluated for the antibacterial activities against Staphylococcus aureus, including Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). Compound 20 shows the most potent activity against the growth of Newman strain, with a MIC value of 0.78 μg/mL, which is comparable with the positive control vancomycin. In addition, compound 20, 21, and 33 are highly antistaphylococcal active against five strains of multidrug-resistant S. aureus, with MIC values of 0.78–1.56 μg/mL. Of note, theses antibacterial active compounds have no obvious toxicity to the viability of human fibroblast (HAF) cells at the MIC concentration.A series of novel 9, 13-disubstituted berberine derivatives have been synthesized and evaluated for the antibacterial activities against Staphylococcus aureus, including Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271).Download high-res image (120KB)Download full-size image

•A series of 2-benzylidenebenzofuran-3(2H)-one derivatives were identified as novel DRAK2 inhibitors.•Preliminary structure activity relationship (SAR) studies were discussed.•Compound 40 showed a favorable selectivity profile for DRAK2 over 26 selected protein kinases.•Compounds 40 and 41 protected islet β-cells from apoptosis in dose-dependent manner.Death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is a serine/threonine kinase that plays a key role in a wide variety of cell death signaling pathways. Inhibition of DRAK2 was found to efficiently protect islet β-cells from apoptosis and hence DRAK2 inhibitors represent a promising therapeutic strategy for the treatment of diabetes. Only very few chemical entities targeting DRAK2 are currently known. We carried out a high throughput screening and identified compound 4 as a moderate DRAK2 inhibitor with an IC50 value of 3.15 μM. Subsequent SAR studies of hit compound 4 led to the development of novel benzofuran-3(2H)-one series of DRAK2 inhibitors with improved potency and favorable selectivity profiles against 26 selected kinases. Importantly, most potent compounds 40 (IC50 = 0.33 μM) and 41 (IC50 = 0.25 μM) were found to protect islet β-cells from apoptosis in dose-dependent manners. These data support the notion that small molecule inhibitors of DRAK2 represents a promising strategy for the treatment of diabetes.Download high-res image (164KB)Download full-size image

•Novel 3,4-seco bile acid amides were designed and synthesized as anticancer agents.•Most compounds displayed more antiproliferative activity than bile acids.•16 showed specific antiproliferative activity against ES-2 (IC50 = 3.11 μM; SI = 20).•27 (IC50 = 1.07 μM; SI = 26.3) inhibited colony forming and induced cell cycle arrest.•27 significantly inhibited migration of PC3M cells in a dose-dependent manner.A series of new seco-A ring bile acid diamides were synthesized, and their antiproliferative activities against PC3M (prostate), HT29 (colon) and ES-2 (ovarian) cancer cell lines were investigated using SRB assays. Most synthesized compounds presented improved antiproliferative activities compared to the parent bile acids (IC50 > 80 μM), especially the piperazine conjugated compound 27 with IC50 values of 1.07, 4.58 and 3.86 μM against PC3M, HT29 and ES-2 cancer cell lines, respectively. In addition, all the tested compounds showed less cytotoxic activity on a noncancerous cell line (HAF), and the most active compound 27 exhibited the highest selectivity (Selectivity Index, SIPC3M = 26.3). Furthermore, 27 could also enhance G1 arrest in PC3M cell, revealed by cell cycle analysis, and increase anti-migration activity on PC3M cells, confirmed by transwell migration assay.

An efficient method for construction of 3-arylquinolin-4(1H)-ones via in situ Meinwald rearrangement/intramolecular reductive cyclization of 2′-nitrochalcone epoxides has been developed. The practical approach is of excellent functional groups compatibility with as high as 98% yield under mild reaction conditions. Trapping and NMR analysis about the key intermediates of the transformation provided insights to propose a plausible mechanism for the intramolecular reductive cyclization. Moreover, further derivation successfully furnished hydroxyl substituted and N-methyl substituted derivatives which may provide a promising potential application in exploring biologically active compounds of 3-arylquinolin-4(1H)-ones.

In our continued efforts to develop lithocholic acid (LCA) analogues as selective PTP1B inhibitors, 14 novel 2,3-pyrazole ring-substituted-4,4-dimethyl derivatives were synthesized and evaluated against PTP1B, as well as homologous protein tyrosine phosphatases (PTPs). All compounds were shown to be more potent and selective PTP1B inhibitors than LCA (IC50 = 12.74 μM) with IC50 values ranging between 0.42 to 4.49 μM. Moreover, treatment of CHO/hIR cells with 4,4-dimethyl-2′-(p-fluoro phenyl)-2′H-chola-2,5-dieno[3,2-c]pyrazol-24-oic acid (30) or 4,4-dimethyl-2′-(o-chloro phenyl)-2′H-chola-2,5-dieno[3,2-c]pyrazol-24-oic acid (34) increased the phosphorylation levels of IR and Akt in a dose dependent manner. The promising findings in this study suggest that further investigation of these compounds for the treatment of metabolic disorders is warranted.

An efficient and practical method for the synthesis of unsymmetric benzils from readily available β-ketoaldehydes has been developed. Various unsymmetric 1,2-diaryldiketones bearing functional groups have been obtained in good to excellent yields under mild reaction conditions. A plausible mechanism was proposed, and α,α-dichloroketone was considered as the key intermediate. The generation of α,α-dichloroketones from β-ketoaldehydes may undergo the following steps: (1) oxidation by sodium hypochlorite, (2) decarboxylation, and (3) chlorination by Cl2 generated from sodium hypochlorite.

•Non-phosphorus-based fructose-1,6-bisphosphatase (FBPase) inhibitors, 2,5-diphenyl-1,3,4-oxadiazoles, were explored.•Compounds bearing a linear alkyl with terminal hydrogen-bonding acceptor showed potent inhibition at molecular level.•Compound 22 and 27b inhibit the glucose production in primary rat hepatocytes with an IC50 value of 167.3 μM and 112.5 μM.•Both inhibition and binding mode to the enzyme were investigated by enzymatic kinetics and in silico experiments.With the aim of discovering a novel class of non-phosphorus-based fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of 2,5-diphenyl-1,3,4-oxadiazoles were synthesized based on the hit compound (1) resulting from a high-throughput screening (HTS). Structure–activity relationship (SAR) studies led to the identification of several compounds with comparable inhibitory activities to AMP, the natural allosteric inhibitor of FBPase. Notably, compound 22 and 27b, bearing a terminal carboxyl or 1H-tetrazole, demonstrated remarkable inhibition to gluconeogenesis (GNG). In addition, both inhibition and binding mode to the enzyme were investigated by enzymatic kinetics and in silico experiments for representative compounds 16 and 22.Novel non-phosphorus-based FBPase inhibitors were explored, and some compounds showed comparable inhibitory activities to AMP and remarkable inhibition to gluconeogenesis. Both inhibition and binding mode to the enzyme were investigated.

An efficient method for preparation of 3-formyl-2-arylbenzo[b]furan derivatives 4 from 3-chloro-2-(2-methoxyaryl)-1-arylprop-2-en-1-one 2 was developed, and the desired product was obtained in good to excellent yields. By converting 2-(2-methoxyphenyl)-3-oxo-3-phenylpropanal 1 to 2, the regioselectivity problem occurring in the reaction when using 1 as the starting material was successfully avoided. Furthermore, a one-pot procedure for the successive demethylation, cyclization, and hydrolysis was evolved, although the intermediate 3-(dibromomethyl)-2-phenylbenzo[b]furan 3a could be isolated. A plausible mechanism was proposed based on some in situ investigations.

Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC50 = 12.74 μM) by a vertical screen for the first time. Further SAR research was carried out by synthesizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and a 14-fold selectivity over the homogenous enzyme TCPTP.The synthesis and biological evaluation of a series of heterocyclic ring-substituted 4,4-dimethyl lithocholic acid derivatives are reported for the first time. The active compound 14b displayed potent inhibitory activity on protein tyrosine phosphatase 1B with IC50 value of approximately 1.62 μM.

A novel organic dye with N-substituted pyridinium as the acceptor and carboxylate as the anchoring group were designed and synthesized for dye-sensitized solar cells, which give solar energy-to-electricity conversion efficiency (η) of up to 3.47% in comparison with the reference Ru-complex (N719 dye) with an η value of 5.27% under similar experimental conditions. This new dye is simple in structure, very easy to synthesize, and gives high Voc.