Exploration of the structure-activity relationship and druggability of novel oxazolidinone-based compounds as Gram-negative antibacterial agents.

To gain further knowledge of the structure-activity relationship and druggability of novel oxazolidinone-based UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) inhibitors as Gram-negative antibacterial agents, compounds containing the hydrophobic tails with different lengths and terminal substitutions were synthesized and their antibacterial activities against standard and clinically isolated Gram-negative strains were evaluated. We summarized their structure-activity relationships and found that oxazolidinone-based compounds exhibited a narrower antibacterial spectrum compared with threonine-based compounds. Furthermore, we parallelly compared the metabolic stabilities of the compounds with the classic threonine scaffold and the novel oxazolidinone scaffold in liver microsomes. The results indicated that the druggability of the oxazolidinone scaffold may be inferior to the classic threonine scaffold in the design of LpxC inhibitors.

Design, synthesis and structure-activity relationship evaluation of novel LpxC inhibitors as Gram-negative antibacterial agents.

LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To develop novel LpxC inhibitors with good antibacterial activities and biological metabolism, we summarized the basic skeleton of reported LpxC inhibitors, designed and synthesized several series of compounds and tested their antibacterial activities against Escherichial coli and Pseudomonas aeruginosa in vitro. Structure-activity relationships have been discussed in this article. The metabolism stability of YDL-2, YDL-5, YDL-8, YDL-14, YDL-20-YDL-23 have been evaluated in liver microsomes, which indicated that the 2-amino isopropyl group may be a preferred structure than the 2-hydroxy ethyl group in the design of LpxC inhibitors.

T33, a novel peroxisome proliferator-activated receptor γ/α agonist, exerts neuroprotective action via its anti-inflammatory activities.

AIM: To examine the neuroprotective effects of T33, a peroxisome proliferator-activated receptor gamma/alpha (PPARγ/α) agonist, in acute ischemic models in vitro and in vivo. METHODS: Primary astrocytes subjected to oxygen-glucose deprivation/reperfusion (O/R) and BV-2 cells subjected to hypoxia were used as a model simulating the ischemic core and penumbra, respectively. The mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were measured using qPCR. The levels of TNF-α secreted by BV-2 cells were measured using ELISA. Protein levels of cyclooxygenase-2 (COX-2), p65, phosphorylated I-κBα/I-κBα, phosphorylated I-κB kinase (pIKK), phosphorylated eukaryote initiation factor 2α (p-eIF-2α)/eIF-2α and p-p38/p38 were detected using Western blot. PPARγ activity was measured using EMSA. The neuroprotection in vivo was examined in rat middle cerebral artery occlusion (MCAO) model with neurological scoring and TTC staining. RESULTS: Addition of T33 (0.5 µmol/L) increased the level of I-κBα protein in primary astrocytes subjected to O/R, which was due to promoting protein synthesis without affecting degradation. In primary astrocytes subjected to O/R, addition of T33 amplified I-κBα gene transcription and mRNA translation, thus suppressing the nuclear factor-kappa B (NF-κB) pathway and reducing inflammatory mediators (TNF-α, IL-1ß, and COX-2). In BV-2 cells subjected to hypoxia, T33 (0.5 µmol/L) reduced TNF-α, COX-2, and p-P38 production, which was antagonized by pre-administration of the specific PPARγ antagonist GW9662 (30 µmol/L). T33 (2 mg/kg, ip) attenuated MCAO-induced inflammatory responses and brain infarction, which was antagonized by pre-administered GW9662 (4 mg/kg, ip). CONCLUSION: T33 exerted anti-inflammatory effects in the ischemic core and penumbra via PPARγ activation, which contributed to its neuroprotective action.

Enantioselective total synthesis of (-)-(S)-stepholidine.

Enantioselective total synthesis of (-)-(S)-stepholidine, a drug candidate for the treatment of schizophrenia and/or drug abuse, is described. Asymmetric transfer hydrogenation of imines with use of Noyori's catalyst was used as the key step and (-)-(S)-stepholidine was synthesized in 6 steps, with 42% overall yield and >99% ee.

[Design and synthesis of a type of benzopyran derivatives with insulin-sensitizing activity].

Ten novel compounds were designed and synthesized on the basis of compound 1, their insulin-sensitizing activities were evaluated in 3T3-L1 cells. Results showed that compound 10 exhibited strong differentiation-stimulating activity on 3T3-L1 cells model, which indicated that compound 10 may possess well insulin-sensitizing activity.

[Design, synthesis and anti-HBV activity of L-amino acid ester prodrugs of acyclic nucleoside phosphonates].

To design and synthesis a series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates with more potent anti-HBV activity, adefovir dipivoxil was used as lead compound, according to the results of enhanced oral bioavailability and antiviral activities of nucleoside L-amino acid ester prodrugs. Eleven novel L-amino acid ester prodrugs of acyclic nucleoside phosphonates were designed and synthesized, their anti-HBV activities were evaluated in HepG2 2.2.15 cells. Eight compounds exhibited antiviral activity, and compound 11 showed the most potent anti-HBV activity and highest selective index in vitro (EC50 0.0952 micromol x L(-1), SI 69523). Moreover, by analyzing the primary structure and activity relationship of these compounds, it could be suggested that L-amino acid ester strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.

[Synthesis and biological activity of a series of benzopyran derivatives].

Thirteen benzopyran derivatives were synthesized and their activity stimulating the differentiation of preadipocytes into adipocytes were evaluated with 3T3-L1 cells. Compound 8 was also tested for its hypoglycemic activity on db diabetes mice model. Results indicated that compounds 3, 8 and 11 exhibited strong differentiation-stimulating activity on 3T3-L1 cells model, and compound 8 can reduce the blood-sugar level of db diabetes mice dramatically.

The potential insulin sensitizing and glucose lowering effects of a novel indole derivative in vitro and in vivo.

Thiazolidinediones (TZDs) such as rosiglitazone are antidiabetic peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma agents improve diabetes by increasing insulin sensitivity and enhancing the differentiation of preadipocytes into adipocytes. The present study aimed to identify if 1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-3-indoleacetitic acid (GY3), a newly synthesized indole compound, could enhance adipocytes differentiation and insulin sensitivity. The results showed that both GY3 and rosiglitazone significantly increased the lipid accumulating of 3T3-L1 adipocytes induced by isobutylmethylxanthine, dexamethasone and insulin mixture, but GY3 (not rosiglitazone) failed to increase the lipid accumulation when induced by insulin alone. In addition, GY3- or rosiglitaozne-induced protein expression of GLUT4 and adiponectin was determined by Western blot analysis. GY3 activated PPARalpha weakly but did not affect PPARgamma, while rosiglitazone activated PPARgamma significantly, suggesting different mechanisms between GY3 and rosiglitazone on adipocyte differentiation. Furthermore, both GY3 and rosiglitazone enhanced the adiponectin and insulin pathway proteins expression and adiponectin secretion in mature adipocytes, but only GY3 not rosiglitazone elevated gene expression of leptin and resistin. Both GY3 and rosiglitazone enhanced glucose consumption in HepG2 cells especially in the presence of insulin. In the in vivo study, GY3 decreased serum glucose and insulin in db/db mice, indicating the insulin sensitizing effect might contribute to its antidiabetic mechanism. Altogether, these results suggest that GY3 could improve insulin resistance and lower glucose level, GY3 and its derivatives might be developed as a substitution therapy for diseases with insulin resistance.

Insulin-sensitizing effects of a novel alpha-methyl- alpha -phenoxylpropionate derivative in vitro.

AIM: To examine the insulin sensitizing effects of a novel alpha-methyl-alpha- phenoxylpropionate derivative YY20 in insulin-sensitive cell lines. METHODS: The peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist bioactivities of YY20 were detected by a preadipocyte differentiation assay. RT-PCR and Western blotting analysis were used to detect the expression of the target gene or protein. The effects of YY20 on insulin-mediated glucose consumption were determined in the HepG2 human hepatocellular carcinoma line. RESULTS: YY20 could enhance the differentiation of preadipocytes to adipocytes and upregulate the gene expression of PPAR gamma 2, as well as the protein expression of insulin receptor substrate- 1 (IRS-1), glucose transporter-4 (GLUT4), and adiponectin (ACRP30). The effects on GLUT4 and ACRP30 could be reversed by the PPAR gamma inhibitor SR-202. Furthermore, YY20 efficiently reduced glucose consumptions in HepG2 cells after 24 h culture, and the effects were related to insulin and YY20 concentrations. CONCLUSION: YY20, a potential insulin-sensitizing agent like rosiglitazone, could enhance glucose consumption in HepG2 cells in a concentration- and insulindependent manner. It may improve the insulin resistance associated with type 2 diabetes.

Recent developments in studies of l-stepholidine and its analogs: chemistry, pharmacology and clinical implications.

Tetrahydroprotoberberines (THPBs) represent a series of compounds extracted from the Chinese herb Corydalis ambigua and various species of Stephania. THPBs, dependent on the presence of hydroxyl groups in its structure, are divided into three types: nonhydroxyl-THPBs, monohydroxyl-THPBs and dihydroxyl-THPBs. THPBs are identified as a new category of dopamine receptor ligands. Among all THPBs, dihydroxyl-THPBs attracted particular attention because of their dual actions on dopamine (DA) receptors. They exhibit D(1) receptor agonistic activity while acting as D(2) receptor antagonists. This unique pharmacological profile made dihydroxyl-THPBs such as l-stepholidine (l-SPD) potential agents in the treatment of drug addiction, Parkinson's disease, and especially, schizophrenia. Clinical studies have shown that co-administration of l-SPD with a typical antipsychotic drug significantly enhances the therapeutic effects and remarkably reduces the tardive dyskinesia induced by the typical antipsychotic drug used with schizophrenic patients. Moreover, l-SPD alone was shown to have therapeutic value without inducing significant extrapyramidal side effects and also seemed to reduce the negative symptoms of schizophrenia. This is confirmed in experimental studies using animal models of schizophrenia, in which l-SPD improved social interaction and cognitive function, inhibited hyperactivity in schizophrenic animals. This review discusses the chemistry, pharmacology and clinical implications of l-THPBs in the drug development for psychosis and neurobiological diseases.

Antidiabetic effect of a novel non-thiazolidinedione PPAR gamma/alpha agonist on ob/ob mice.

AIM: To study whether T33, a new synthesized non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR) gamma/alpha dual agonist has an antidiabetic effect on ob/ob mice. METHODS: Ob/ob mice were treated with 4 mg/kg or 8 mg/kg T33 by gavage for 20 d. Blood glucose levels were measured regularly. An oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT) were preformed on d 8 and d 12, respectively. The levels of insulin, triglyceride and free fatty acid (FFA) in the serum were measured at the end of administration. The intramuscular and liver triglyceride content was also determined. RESULTS: T33 reduced the hyperglycemia, hyperinsulinemia and hyperlipidemia of the ob/ob mice. The OGTT and ITT showed that the insulin resistance state of the ob/ob mice was obviously ameliorated after T33 treatment. After 20 d treatment with 8 mg/kg T33, the triglyceride content in the gastrocnemius muscle decreased significantly. T33 did not have any effect on triglyceride content in the liver, whereas rosiglitazone significantly increased the hepatocyte lipid deposition. CONCLUSION: The PPARgamma/alpha dual agonist T33 has antidiabetic and insulin-sensitizing effects in ob/ob mice. It has the potential to be a new therapeutic candidate for the treatment of type 2 diabetes.

[Design, synthesis and insulin-sensitizing activity of indole derivatives].

AIM: To design and synthesize compounds with insulin-sensitizing activity. METHODS: Using association principle of drug design, ten title compounds were designed and synthesized on the basis of known compounds with insulin-sensitizing activity, and their insulin-sensitizing activity were evaluated on 3T3-L1 pre-adipocyte cells. RESULTS: One of the synthesized compounds showed strong insulin-sensitizing activity in vitro. CONCLUSION: This compound may possess good sugar-lowering activity, and will be chosen for further hypoglycemic evaluation in vivo.