A practical synthesis of sarpogrelate hydrochloride and in vitro platelet aggregation inhibitory activities of its analogues

<正>A convenient approach for the preparation of sarpogrelate hydrochloride was developed.Two series of sarpogrelate hydrochloride analogues were designed and synthesized in order to improve their platelet aggregation inhibitory activities, biological tests suggested that these compounds have platelet aggregation inhibitory activities to some extent.     

Syntheses and bioactivities of mixed butyl/cyclohexyl tin carboxylates

Eight novel compounds have been synthesized and they are two series of mixed tri(butyl/cyclohexyl) tin carboxylates:Bu_nCy_(3-n) SnO_2CR (n=1,2;R=n-C_3H_7,C_6H_5,4-ClC_6H_4,4-NO_2C_6H_4).Inaddition to the studies of their structures with IR,~(119)Sn and ~(13)C NMR,we tested their fungicidal,insec-ticidal and acaricidal activities.The percentage of inhibition to the aforementioned phytopathogen isabout 80—100% at 50 ppm in glasshouse and 100% for T.Uriticae at 500 ppm.Those findingsindicate that this kindof compounds have both fungicidal and acaricidal activities and mayhave a goodprospect for applications.     

Synthesis and fungicidal activity study of novel daphneolone analogs with 2,6-dimethylmorpholine

A series of novel daphneolone analogs was designed and synthesized on the basis of natural product 1,5-diphenyl-2-penten-1-one(I) from Stellera chamaejasme L. as lead compound, whereby 2,6-dimethylmorpholine moiety was introduced to replace 1-phenyl group. Their structures were confirmed by IR,1H NMR, and HRMS(ESI) or elemental analysis,13 C NMR for some representative compounds. The two isomers of target compounds were separated and identified by NOESY technique and chemical method.All of the synthesized compounds have been evaluated for anti-plant pathogenic fungi activities. The results showed that some compounds exhibited moderate to good antifungal activities against tested fungi at the concentration of 50 mg/L. Among them, compound 7d, with a 4-bromine-substituted phenyl group and cis-2,6-dimethylmorpholine moiety, displayed best activity with an EC50 of 23.87 mmol/L against Valsa mali, superior to lead compound I. In addition, preliminary structure–activity relationship analysis indicated that, between two isomers of target compounds, the antifungal activities of the isomer with cis-2,6-dimethylmorpholine were better than the trans-isomer.     

Synthesis and antitumor activities of structure-related small molecular compounds of gambogic acid

Through simplifying the complicated skeleton of the natural product gambogic acid, two series derivatives of chromone and xanthone were synthesized and examined for their antitumor activities against several cancer cells in vitro by MTT method. The results showed that appropriate introduction of prenyl group to the small molecular compounds could elevate their antitumor activities. The structure-activities relationship of synthesized compounds certified that the bridgecore in gambogic acid was very important for keeping its antitumor activities.     

Steroid-bismetalloporphyrin as enzyme model of cytochrome P-450 monooxygenase

The model compounds of androgenic steroid-bismetallopor-phyrins 3a-3d and androgenic monometalloporphyrins 2a-2d have been synthesized. Catalytic study in two-phase condition on epoxidation of styrene under the catalysis of model catalysts shows (hat the catalytic performances of steriod-bismet-alloporphyrin is superior to steroid- metalloporphyrin and the corresponding simple metalloporphyrin. The excellent catalytic property of steriod-bismetallopotphyrin can be rationalized as the hydrophobic action of steroid framework and the cooperative action of two metalloporphyrins in catalysis.     

A Novel Palladium-Catalyzed Reaction and Its Application in Preparation of Derivatives of Stilbazols

Many derivatives of stilbazoles have strong biological activities and pharmacological actions. For instance, (-substituent-(E)-4-styrylpyridines can be used as cytokinin analogues1. A series of N-substituted tetrahydro (phenylethenyl) pyridine derivatives were reported in vitro against both nicotinic and muscarinic receptors derived from rat cerebral cortax2. Therefore they can be used as candidates to develop new drugs for treatment of some diseases. On the other hand, this kind of compounds…     

Synthesis and biological evaluation of indole-3-carboxamide derivatives as antioxidant agents

A novel series of indole-3-carboxamide derivatives (6a-6l) have been designed, synthesized and evaluated for their antioxidant activity against human neuroblastoma SH-SY5Y cell line using H2O₂ radical scavenging assay. Biological activity evaluation showed that compounds 6a, 6f and 6i exhibited significant in vitro activities, which could have the potential to be developed for novel antioxidants.     

Synthesis and Mesomorphic Properties of Novel γ-Substituted β-Diketonates

The synthesis and mesomorphic properties of two series of novel γ-substituted β-diketonates have been reported. All of the compounds 2,4-dioxo-3-pentyl 4-[[4-(n-alkoxyl) cinnamoyl]oxy]cinnamatetes Ia-If (n=7-12) exhibit two monotropic phases(N and Sc) and have a wider mesophase range than the compounds 2,4-dioxo-3-pentyl 4-[[4-(n-alkoxyl) benzoyl]oxy] cinnamatetes Ⅱa-Ⅱf (n=7-12), which display one monotropic nematic phase (n=7-10) or an enantiotropic nematic phase for n=11 or two enantiotropic phases (N and Sc)for n=12.     

Design and Synthesis of New Arylsulfonamide and Arylamide Derivatives for the Platelet Aggression Inhibitor

A series of arylsulfonamide and arylamide derivatives have been prepared from anisole in good yields.The structures of those compounds were confirmed by ^H-NMR and MS analysis.Their activities against platelet aggregation were tested in vitro by using the Born test on rabbits.     

A New and Efficient Synthesis of 2H-3, 1-Benzoxazine Compounds

2H-3, 1-Benzoxazine heterocyclic compounds are a series of potent nonsteroidal pro- gesterone receptor agonists1-3 and have many other applications such as carbonaceous electrode, plant growth regulating and anti-stress activities4-6, etc.. Comparing to other benzoxazine series, such as 1, 4-benzoxazine, 2H-1, 3-benzoxazine, etc., little attentions have been paid for this series of compounds. There is only one method for the preparation of 2H-3, 1-benzoxazine, e.g. cyclocondensation of o-amin…     

Synthesis of novel β-amino ketones containing a p-aminobenzoic acid moiety and evaluation of their antidiabetic activities

The synthesis of two series of β-amino ketones containing a p-aminobenzoic acid moiety (TM-1 and TM-2) using a modified protocol of the Mannich reaction is reported. The molecular structures of a total of tweenty three new target compounds were characterized by 1H NMR, 13C NMR, ESI-MS and HR-MS. Subsequently, their antidiabetic activities were screened in vitro. The α-glucodase inhibition (α-GI) activity of compound 1e reached a remarkable level of 66.50%. The peroxisome proliferatoractivated receptor (PPAR) relative activation activities of six compounds are above 80%, and in particular 2i displays an unprecedentedly high PPAR of 130.91%. The structure-activity relationships of the compounds were established. 2i is also subject to further in-depth investigation.     

Synthesis and structure-activity relationships study of α-aminophosphonate derivatives containing a quinoline moiety

Two series of a-aminophosphonate derivatives containing a quinoline moiety have been designed and synthesized by introducing bioactive quinoline scaffold to a-aminophosphonate. The in vitro cytotoxic activities of target compounds were first investigated against two human cancer cell lines including Eca109 and Huh7 by MTT assay. Results revealed that most of target compounds exhibited moderate to high antitumor activities against the tested cancer cell lines and some demonstrated more potent inhibitory activities compared with Sunitinib. Among them, compounds 4b2 and 4b4 containing methylsubstituted aniline group were found to be more active than Sunitinib against both of two cancer cell lines, with IC50 in the range of 2.26 mmol/L–7.46 mmol/L.     

Syntheses of Lactam Derivatives of Chenodeoxycholic Acid and in vitro Antiproliferative Activity

With chenodeoxycholic acid as starting material,a series of lactam derivatives of chenodeoxycholic acid was synthesized and their antiproliferative activities against some cancer cells were determined.Among the synthesized derivatives,compounds 6 and 18 displayed distinct antiproliferative activity against PC-3,H-292,SKBR3 and Hey-1B cancer cells,and compounds 10,17 and 18 showed significant antiproliferative activity against SKBR3 cells.Our results reveal that the position of hydroximino on ring A or B of the parental scaffold dramatically affects the antiproliferative activity of these compounds.The conversion of 7-hydroximino to other substituent or 7-hydroximino to 3-hydroximino in the compounds resulted in a dramatic decrease of the antiproliferative activity,suggesting the importance of 7-hydroximino group for the biological activity of the compounds.The structure/activity correlation generated from the studies provides valuable information for the further design of novel chemotherapeutic drugs.     

Design, syntheses and biological activity of novel ALS inhibitors (Ⅸ)——CoMFA of sulfonylureas and triazolopyrimidine-2-sulfonamides ALS inhibitors

Quantitative structure-activity relationships for herbicidal activity against rape of sulfonylurea and triazolopyrimidin-2-sulfonamide derivatives were examined three-dimensionally using comparative molecular field analysis (CoMFA). The CoMFA results show that the slopes in steric and electrostatic fields around the molecule were significant for both series in governing the potency variations in herbicidal activity. Based upon the successful superposition between the two series, the herbicidal activity was analyzable with a single equation for the combined set of compounds, which suggested that the two different series of compounds have a common region of the receptor site.     

Synthesis and Antimicrobial Activity of Some New 4H-Pyrrolo[1,2-a]benzimidazoles

Some new 4H-pyrrolo[1,2-a]benzimidazoles（2a-2f） have been synthesized. The structures of these compounds were confirmed by IR, tH NMR, mass spectroscopy and elemental analysis. Compound 2a was further confirmed by X-ray diffraction. The in vitro antimicrobial activities of these compounds were determined against some gram-positive bacteria, gram-negative bacteria and fungi and their drug-resistant isolates in comparison with standard drugs. Antimicrobial results indicate that compounds 2c, 2d and 2e show moderately active antibacterial properties, their minimum inhibitory concentrations are from 12.5 μg/mL to 125 μg/mL. In the series, the most active compound against C. albicans is compound 2fwith an MIC value of 31.25 μg/mL.     

Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures,a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-allkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3 H)-ones were designed,synthesized and evaluated for their antiviral activities in MT-4 cells.Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC_(50) values ranging from 7.55 μmol/L to 0.018 μmol/L.Among them,compound 5 c was identified as the most promising inhibitor against HIV-1 replication with an IC_(50)=0.018 μmol/L,CC_(50)=194 μmol/L,and SI=12791,which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV.In addition,5 c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02.The preliminary structure-activity relationship(SAR) and molecular modeling studies were also discussed,which provides some useful indications for guiding the further rational design of new S-DACO analogues.     

Drug discovery based on the structure of FKBP12: Design, synthesis and evaluation of L-1,4-thiazane-3-carboxylic acid derivatives as neuroimmunophilin ligands

By choosing neuroimmunophilin FKBP12 as a therapeutical target, we have attempted to discover a new structural drug for treating neurodegenerative disease. This drug should possess neurotrophic activity and not affect the immune system. Based on the crystal structure of FKBP12, FK506 and Calcineurin complex, a series of small organic molecules were designed. These molecules were to have the ability of binding to FKBP12 in a virtual screening. By using a solution parallel synthetic method, these compounds were synthesized. The neuroprotective and neuroregenerative activities of these compounds were evaluated by binding assays, PC12 cells survival and neurite outgrowth model, chick dorsal root ganglion cultures (DRG) and 6-OHDA lesioned mice sympathetic nerve endings model. The evaluation results of these compounds showed that compound N308 has great promise as a candidate for a neuroprotective and neuroregenerative agent.     

Synthesis and Primary Research on Antitumor Activity of Three New Panaxadiol Fatty Acid Esters

For making use of Ginseng resources that exhibit an antitumor activity and for finding new anticancer drugs,three new fatty acid ester compounds: 3β-acetoxy panaxadiol ( Ⅰ ), 3β-palmitic acid aceloxy panaxadiol ( Ⅱ ), and 3β-octadecanoic acid aceloxy panaxadiol( Ⅰ , Ⅱ , and Ⅲ ) were synthesized with panaxadiol, diacetyl oxide, palmityl chloride and stearyl chloride, and their structures were determined via MS, 13C NMR, IR, TLC, and so on. The molar yields of the three compounds are 75.14%, 79. 08%, and 72. 57%, respectively. Meanwhile, the antitumor activity of the three new panaxadiol fatty acid ester derivatives and panaxadiol was compared by using the method of MTT. Tumor cell used was Vero cell line. Positive control was 5-FU, blank was an RPMI1640 culture medium, negative control was an RPMI1640 culture medium and the solvent for drugs to be tested. Compound Ⅰ has the strongest antitumor activity followed by panaxadiol; compounds Ⅱ and Ⅲ have similar and weakest antitumor activities.Furthermore, the antitumor activities of the panaxadiol fatty acid ester derivatives show positive correlation with the concentration of the test group, but show no relationship with the molecular weight of fatty acid. The methods that are used to synthesize the three compounds with high yields and strong antitumor activities are simple and show a great potential for meeting the needs of industrial manufacture of these drugs.     

Triazole and Benzotriazole Derivatives as Novel Inhibitors for p90 Ribosomal S6 Protein Kinase 2： Synthesis, Molecular Docking and SAR Analysis

A series of triazole and benzotriazole derivatives as novel p90 ribosomal S6 protein kinase 2 （RSK2） inhibitors were designed and synthesized. The in vitro activities against RSK2 were evaluated, and among 14 compounds, compounds 5, 6, 11, 12, 13 and 14 exhibited enzyme IC50 values of 8.91, 2.86, 3.19, 3.05, 4.49 and 2.09 μmol/L re- spectively. The proposed binding modes were simulated using molecular docking method, and the docking results coupled with the stmcture-activi1：y relationship （SAR） analysis indicated that all these active compounds bound to the RSK2 ATP binding site at NTKD, and the electron-donating groups on the 4-position of phenyl were the deter- minant point for the inhibitory activity.     

Synthesis of 5—Aryl—1,2—dihydro—1—pyrrolizinones

In order to search for new potent anti-inflammatory and analgesic agents in pyrrolizinones,the title compounds were designed and synthesized.A series of the compounds were prepared with two different synthetic schemes.Some of the compounds showed remarkable anti-inflammatory and/or analgesic activities on mice.