•Structural modification of a lead compound 1a was conducted successfully.•General improvement of anti-bacterial activity was observed.•Compound 2b shown excellent activities with MIC = 0.098–0.78 μg/mL.The synthesis of (S)-2-(4-tert-butylphenoxy)-3-(benzoxazol-5-yl) propanoic acid derivatives (2a-k) were described and their in vitro antibacterial activities were determined against Gram-negative and -positive bacteria. These compounds were found to exert a broad spectrum of activity against the screened bacteria, but poor MIC values were found for Candida albicans fungi. Compound 2b bearing a hydrophobic aromatic tie was the most active derivative against all bacteria studied with MIC values ranging from 0.098 to 0.78 μg/mL. The activity of 2b against B. subtilis was 2-fold higher than Penicillin, and 8- to 510-fold higher than other control antibiotics.Structural modification of lead compound 1a.Download high-res image (136KB)Download full-size image

•A new class of nonionic PTP1B inhibitors was found.•They are highly potent and moderately selective.•They have great potential in penetrating cellular membranes.•They interact with multiple secondary binding sites of PTP1B.Known PTP1B inhibitors with bis-anionic moieties exhibit potent inhibitory activity, good selectivity, however, they are incapable of penetrating cellular membranes. Based upon our finding of a new pharmacophoric group in inhibition of PTP1B and the structural characteristics of the binding pocket of PTP1B, a series of bis-arylethenesulfonic acid ester derivatives were designed and synthesized. These novel molecules, particularly Y-shaped bis-arylethenesulfonic acid ester derivatives, exhibited high PTP1B inhibitory activity, moderate selectivity, and great potential in penetrating cellular membranes (compound 7p, CLog P = 9.73, Papp = 9.6 × 10-6 cm/s; IC50 = 140, 1290 and 920 nM on PTP1B, TCPTP and SHP2, respectively). Docking simulations suggested that these Y-shaped inhibitors might interact with multiple secondary binding sites in addition to the catalytic site of PTP1B.The optimization of aryl ethenesulfonic acid esters for PTP1B inhibition.Download high-res image (92KB)Download full-size image

•Disclosed 5-azaquinoxaline-2,3-diones as novel noncarboxylic DAAO inhibitors.•Confirmed the analgesic effects of DAAO inhibitor based on a new scaffold.•Provided a new class of chemical entities for potential analgesic application.A series of 5-azaquinoxaline-2,3-dione derivatives were synthesized and evaluated on d-amino acid oxidase (DAAO) inhibition as potential α-hydroxylactam-based inhibitors. The potent inhibitory activities in vitro suggested that 5-nitrogen could significantly enhance the binding affinity by strengthening relevant hydrogen bond interactions. The analgesic effects of intrathecal and systemic injection of 8-chloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione, a representative molecule of 5-azaquinoxaline-2,3-dione, were investigated in rodents. This research not only confirmed the analgesic effect of the DAAO inhibitors but provided a new class of chemical entities with oral application potential for the treatment of chronic pain and morphine analgesic tolerance.Systemic injection of 8-chloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (Compound 16), a novel potent d-amino acid oxidase (DAAO) inhibitor, inhibited formalin-induced tonic pain in rodents in a dose-dependent manner.

•A series of benzisothiazolylpiperazine derivatives were synthesized.•Target compounds were evaluated affinities for D2, D3, 5-HT1A and 5-HT2A receptors.•The proming compound 9j had low affinities for M1 receptors and hERG channels.•9j showed in vivo activities in animal models with low potential for catalepsy.•9j displayed favorable brain penetration.A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.

The kilogram-scale synthesis of a D2/5-HT2A receptor dual antagonist (±)-SIPI 6360 was developed as an alternative treatment for schizophrenia. Specifically, three conditions were modified and optimized, including the Vilsmeier conditions, to prepare quinoline 3. In addition, the palladium-catalyzed hydrogenation was modified to synthesize dihydroquinolin-2(1H)-one 5, and the reduction of β-chloroamide was altered to form 3-chloropropanamine 8. Ultimately these improvements led to the preparation of a 1.5 kg of (±)-SIPI 6360 batch in eight steps with an overall yield of 34% and purity of 99.8%.

Ultrafiltration-based affinity selection combined with liquid chromatography-mass spectrometry (LC-MS) is an efficient tool for screening complex mixtures, such as traditional medicines. And this approach has many advantages over the more conventional bioassay-guided isolation, which is time-consuming and laborious. This paper presents an application of an ultrafiltration-based LC-MS approach to screen potential protein tyrosine phosphatase 1B (PTP1B) inhibitors from Chinese red yeast rice (RYR), and the reliable potential active compounds were determined based on the optimized evaluation criteria of binding behavior. As a result, at least one compound in the RYR extract was identified as a potential PTP1B inhibitor, and its structure was confirmed to be that of monascorubramine using mass spectrometry elevated energy (MSE). The binding behavior of monascorubramine to T cell protein tyrosine phosphatase (TCPTP, a homolog of PTP1B) and other randomly chosen proteins (proprotein convertase subtilisin/kexin type 9, PCSK9; low-density lipoprotein receptor, LDLR; phosphomannomutase 2, PMM2; serine hydroxymethyltransferase, SHMT; bromodomain-containing protein 4 domain 1, BRD4-1; and jumonji domain-containing 2A, JMJD2A) was evaluated. RYR was verified to exhibit a selective PTP1B inhibitory activity, partially because monascorubramine showed selectivity towards PTP1B versus TCPTP and the other randomly chosen proteins.

•Potent Staphylococcus aureus Sortase A inhibitors were designed and synthesized.•Most compounds exhibited excellent inhibitory activity (IC50 = 19.8–184.2 μM).•The structural activity relationship (SAR) and molecular docking studies were revealed.A series of novel 2-phenyl-benzo[d]oxazole-7-carboxamide derivatives were designed, synthesized and evaluated for their in vitro inhibitory activities against Staphylococcus aureus Sortase A with known Sortase A inhibitor pHMB as positive compound (IC50 = 130 μM). Most compounds exhibited excellent inhibitory activity (IC50 = 19.8–184.2 μM). Structure–activity relationship studies demonstrated that substitution at 7-position and 2-position of benzoxazole had great influence on the activities. Specifically, the substituent at 7-position is indispensable for inhibitory activity. The molecular docking studies revealed the i-butyl amide group went towards the β6/β7 loop-β8 substructure of the protein and the benzoxazole core lied in a hydrophobic pocket composed of Ala118, Val166, Val168, Val169 and Ile182, shaping the whole molecule into a L-shape mode to be recognized by Sortase A.Thirty-one 2-phenyl-benzo[d]oxazole-7-carboxamide derivatives were designed and synthesized as potentially potent Staphylococcus aureus Sortase A inhibitors. Most compounds exhibited excellent inhibitory activity (IC50 = 19.8–184.2 μM). The structural activity relationship (SAR) of these compounds demonstrated that substitution at 7-position and 2-position of benzoxazole has great influence on the inhibitory activities. The molecular docking studies revealed the i-butyl amide group and the benzoxazole core shaped the whole molecule into a L-shape mode to be recognized by Sortase A.

A series of 3-substituted-imine-6-hydroxy-benzofuran derivatives were chemically synthesized and biologically evaluated as antibacterial and antifungal agents against Candida albicans, Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus and Bacillus subtilis. Most compounds showed a selective antibacterial activity to gram-positive bacteria and four compounds revealed great antibacterial activities against methicillin-resistant Staphylococcus aureus comparing to the positive control (Ceftazidime) with MIC80 = 12.5–25 μg/mL. Structure-activity relationship studies demonstrated that the free hydroxy group at the C-6 position is essential to the antibacterial activity, and the aromatic imine fragment at the C-3 position also greatly increases antibacterial activity.

We have developed a new approach of affinity selection based on the strategy of rate-zonal density gradient centrifugation combined with the application of an ultra-performance liquid chromatography coupled quadrupole time-of-flight mass spectrometer. In this method, a discontinuous gradient of sucrose solution is used as the centrifugal medium, and the mixed proteins and compounds are laid on the top of it; an applied centrifugal driving force is then used to separate the mixed proteins and their respective ligands in the gradient. Ligand binding ability is defined by comparing the concentration distribution of compounds with the respective concentration distribution of targets after centrifugation once the solution is fractionated. Ideally, a specific ligand would essentially distribute identically with its targeted proteins. This method could be used to screen multiple targets simultaneously, and it would be especially helpful to screen multi-target directed ligands that can interact with multiple targets for specific pathogenesis.

A new and efficient synthesis of tricyclic 4-pyridone analogs through the intramolecular Heck coupling cyclization was described. This reaction features mild conditions and good functional group tolerance allowing for the preparation of several novel tricyclic 4-pyridone analogs.

Thirty-two 2-substituted ethenesulfonic acid ester derivatives were designed, synthesized, and evaluated for their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) and selectivity over T-Cell protein tyrosine phosphatase (TCPTP). Preliminary structure–activity relationship studies demonstrated that the substitution at the aromatic center and the length of linker between the hydrophobic tail and aromatic center markedly affected the inhibitory activity against PTP1B and the selectivity over TCPTP. Specifically, compounds 43 and 36 revealed excellent inhibitory activity to PTP1B with IC50 = 1.3 μM and 1.5 μM, respectively, and marked 10- and 20-fold selectivity over TCPTP. Cytotoxicity data showed low cytotoxicity for COS-7 cell with IC50 values >100 μM for most synthesized chemicals.Graphical abstractWe confirmed that the substitution at the aromatic center and the length of linker markedly affected the inhibitory activity against PTP1B and its selectivity over TCPTP.Highlights► Thirty-two 2-substituted ethenesulfonic acid ester derivatives were prepared. ► Most compounds exhibited excellent inhibitory activities against PTP1B with IC50 values of 1.3–15.1 μM. ► The substitution at the aromatic center and the length of linker markedly affected the inhibitory activity against PTP1B. ► Most chemicals have low cytotoxicity for COS-7 cell with IC50 values >100 μM. ► Compounds 43 and 36 marked 10- and 20-fold selectivity over TCPTP respectively.

The traditional methods for dipeptidyl peptidase IV (DPP-IV) inhibitor screening using fluorescence and chromogenic detections have a number of limitations. Interference with assay readout may occur if compounds have strong absorption at the wavelength region used for the detection. Some commonly used fluorescent and chromogenic DPP-IV substrates have poor aqueous solubility and require organic solvents such as DMSO for solubilization. The use of organic co-solvents in enzymatic assays for DPP-IV may lead to unreliable results. Furthermore, some fluorescent and chromogenic DPP-IV substrates are unstable in aqueous solution and undergo hydrolysis in the absence of DPP-IV. We have developed an LC-MS based method for DPP-IV activity assay which allowed the use of wider selections of substrates than the fluorescent and chromogenic methods. The LC-MS method was validated with several known DPP-IV inhibitors in comparison with a chromogenic assay method and was used to test library compounds to discover new inhibitors of DPP-IV. In addition, being a more universal detection technology, LC-MS method facilitates the discovery of new substrates. A mini-library of tripeptides was synthesized and screened for the discovery of new substrates with improved properties for DPP-IV assay.

Thirteen compounds, based on benzofuran skeleton bearing aryl substituents at its C-3 position through methanone linker, were synthesized and screened for their antibacterial and antifungal activities against four bacteria Escherichia coli, Staphylococcus aureus, Methicillin-resistant S.aureus, Bacillus subtilis, and a fungus Candida albicans. Four hydrophobic benzofuran analogs were found to exhibit favorable antibacterial activities (MIC80 = 0.39–3.12 μg/mL), which were better than the control drugs.Synthesis, characterization, antibacterial and antifungal properties of some novel benzofurans have been described.Highlights► We synthesized a new series of benzofuran analogues with aryl substituents at its C-2 and C-3 positions. ► Their in vitro antibacterial activities were evaluated against four types of bacteria and one fungus. ► The hydrophobic benzofuran analogues exhibit favorable antibacterial activities, which were better than the positive control drugs.

Chiral 2-(substituted-hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic acid derivatives were synthesized and their antibacterial activities were evaluated against fungus, Gram-negative and Gram-positive bacteria. In general, these compounds showed in vitro activities against all screened Gram-negative and Gram-positive bacteria, but poor MIC values for fungus Candida albicans. Remarkably, the (S)-configuration-substituted phenoxyl side chain on position 2 of propanoic acid exerted excellent antibacterial activity against all screened bacteria. Preliminary structure–activity studies revealed that the hydrophobic substitutes, para-tert-butyl (11r), para-phenyl (11s) and para-benzyloxy (11t) on the phenoxyl side chain displayed best activities against all Gram-negative and Gram-positive bacteria with MIC values between 1.56 and 6.25 μg/mL.Highlights► Novel 2-(substituted-hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic acids were synthesized. ► (S)-Configuration substituted-phenoxyl derivatives exerted excellent antibacterial activity. ► Hydrophobic compounds 11r, 11s and 11t shown great activities with MIC = 1.56–6.25 μg/mL.

A new application of ionic liquids in the preparation of fluorescence probe 5,5′-bis-8-phenylamino-1-naphthylsulfonate (bis-ANS) is represented. The method for the preparation of fluorescence probe bis-ANS in alkyl imidazolium cationic liquids under acidic conditions is described. The effects on reaction yields under different concentration of sodium nitrite and different ionic liquid were studied and good yields were achieved.

In Gram-positive bacteria, Sortase A (Srt A) is a critical cysteine transpeptidase that is responsible for recognizing and assembling surface virulence proteins through the recognition of a LPXTG (leucine, proline, X, threonine, and glycine, where X is any amino acid) signal. Mutants lacking genes for Srt A attenuate infections without affecting microbial viability. Here a series of 2-phenyl-benzofuran-3-carboxamide derivatives were synthesized and identified as potent Srt A inhibitors. Activity assays revealed that multiple compounds exhibited excellent inhibitory activity against Srt A compared with known Sortase A inhibitor pHMB (IC50 = 130 μM). Structural activity relationships (SARs) demonstrated that the amide group at 3-position was essential for inhibitory activity. Replacement of the hydroxyl group at the 2-phenyl position of benzofuran with other substitutions such as a methoxyl, halogen or nitro group reduced the enzyme inhibitory activity in most cases. The compound Ia-22 was found to be the most potent inhibitor against the enzyme with an IC50 value of 30.8 μM. Molecular docking studies showed Ia-22 shared similar binding pattern with substrate LPXTG in the binding pocket of Srt A (PDB: 2KID) including i-butyl stretching, L-shape pattern kinking, and H-bond interaction with Srt A functional site residues Cys184, Trp194 and Arg197.

The traditional methods for dipeptidyl peptidase IV (DPP-IV) inhibitor screening using fluorescence and chromogenic detections have a number of limitations. Interference with assay readout may occur if compounds have strong absorption at the wavelength region used for the detection. Some commonly used fluorescent and chromogenic DPP-IV substrates have poor aqueous solubility and require organic solvents such as DMSO for solubilization. The use of organic co-solvents in enzymatic assays for DPP-IV may lead to unreliable results. Furthermore, some fluorescent and chromogenic DPP-IV substrates are unstable in aqueous solution and undergo hydrolysis in the absence of DPP-IV. We have developed an LC-MS based method for DPP-IV activity assay which allowed the use of wider selections of substrates than the fluorescent and chromogenic methods. The LC-MS method was validated with several known DPP-IV inhibitors in comparison with a chromogenic assay method and was used to test library compounds to discover new inhibitors of DPP-IV. In addition, being a more universal detection technology, LC-MS method facilitates the discovery of new substrates. A mini-library of tripeptides was synthesized and screened for the discovery of new substrates with improved properties for DPP-IV assay.