Synthesis of some heteroaryl pyrazole derivatives and their biological activities

In order to search for novel fungicides with high activity, a series of heteroaryl pyrazoles were synthesized from 5-pyra-zole formhydrazide. The structures of all new compounds were confirmed by spectroscopic methods and microanalyses. Preliminary bioassays indicated that some compounds showed fungicidal activity against Puccinia tritinia and PGR activity as well.     

Design and synthesis of novel antifungal triazole derivatives with good activity and water solubility

In order to find novel antifungal agents with good activity and aqueous solubility,a series of SYN-2869 analogues containing a pyridine ring were synthesized and evaluated for their in vitro antifungal activity and water solubility.The results indicated that some compounds showed potent activity against six pathogenic fungi.In particular,the analogue 17a having an isobutyl substitution on the triazolone exhibited significant broad spectrum antifungal activity.In addition,the water solubility of compound 17a was sufficiently improved over SYN-2869.     

Design, Synthesis, and Hypnotic Activity of Pyrazolo [1,5-a]pyrimidine Derivatives

On the basis of the Zaleplon structure, novel pyrazolo[1,5-a]pyrimidines were designed and prepared for studies on their hypnotic activity. This paper reported the synthesis of twelve new 5-methyl-7-substituted-pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives by using simple starting materials such as propane dinitrile and triethyl orthoformate. The structures of the derived target compounds were confirmed by their IR and ^1H-NMR spectroscopic data. The preliminary pharmacological evaluations indicated that some compounds showed hypnotic activity, whilc derivative 1c was the most potent one.     

Metal complexes of anthranilic acid derivatives: A new class of noncompetitive α-glucosidase inhibitors

Metal complexes of anthranilic acid derivatives that constitute a novel class of non-sugar-type aglucosidase inhibitors were synthesized and assessed in vitro for inhibitory activity. All of the Ag(I)complexes(9–16) inhibited a-glucosidase at the nanomolar scale, while 3,5-dichloroanthranilic acid silver(I)(9) was the most potent(IC_(50)= 3.21 nmol/L). Analysis of the kinetics of enzyme inhibition indicated that the mechanism of the newly prepared silver complexes was noncompetitive. The structure-activity relationships were also analyzed, and they are discussed in this report.     

Quantitative Structure Activity Relationship Studies of Benzoxazinone Derivative Antithrombotic Drug Using New Three-dimensional Structure Descriptors

A novel three-dimensional holographic vector of atomic interaction field(3D-HoVAIF) was used to describe the chemical structures of 23 benzoxazinone derivatives as antithrombotic drugs.Here a quantitative structure activity relationship(QSAR) model was built by partial least-squares(PLS) regression.The estimation stability and prediction ability of the model were strictly analyzed by both internal and external validations.The correlation coefficients of established PLS model,leave-one-out(LOO) cross-validation,and predicted values versus experimental ones of external samples were R2=0.899,RCV2=0.854 and Qext2=0.868,respectively.These values indicated that the built PLS model had both favorable estimation stability and good prediction capabilities.Furthermore,the satisfactory results showed that 3D-HoVAIF could preferably express the information related to the biological activity of benzoxazinone derivatives.     

Synthesis and biological activities of(E)-β-farnesene analogues containing 1,2,3-thiadiazole

In order to discover novel compounds with high-activity to control aphid,a series of novel(E)-β-farnesene analogues containing 1,2,3-thiadiazole were designed and synthesized,and their structures were confirmed by IR,~1H NMR,~(13)C NMR,and HRMS(ESI).The stability of representative compounds was studied by HPLC and ~1H NMR techniques.Repellent activity results indicated that compounds 8h and 8j displayed 60.3%and 62.0%repellent rates,respectively.The aphicidal bioassay results showed that most analogues exhibited considerable aphicidal activity against Myzus persicae.Especially,analogues 81,8s and 8t exhibited high activity with LC_(50) values of 33.4 μg/mL,50.2 μg/mL and 61.8 μg/mL,respectively,which were higher than the lead compound(E)-β-farnesene,but lower than commercial insecticide pymetrozine with a LC_(50) of 7.1 μg/mL     

新的依托泊苷衍生物作为细胞毒药物的设计, 合成和生物活性评价

Five novel compounds composed of etoposide and 5-fluorouracil derivatives joined by an ester linkage were prepared and evaluated for their antitumor potential. Most of these analogues have exhibited promising in vitro cytotoxic activity against cell cultures of murine leukaemia P-388 and human lung carcinoma A-549. The results presented herein challenged the long-standing structure-activity relationships, which proposed that a free 4＇-hydroxyl group is essential structural requirement for etoposide-like activity. And in addition, the 4＇-position was suggested to tolerate chemical modifications such as esterification. The preliminary testing results also indicated that the design and synthesis of these compounds were beneficial for therapeutic values of etoposide.     

Synthesis and antibacterial activity of pleuromutilin derivatives with novel C(14) side chain

In order to find novel antibacterial agents with superior antibacterial activity and overcoming multidrug resistance,a series of pleuromutilin derivatives with novel C(14) side chain were synthesized and evaluated for their in vitro antibacterial activities.The results of antibacterial acticities indicated that most of the derivatives showed potent activities against Gram-positive organisms.In particular,compound lOd exhibited the most potent inhibitory activity compared with pleuromutilin and linezoid,emerged as potential molecule for further investigation.     

Novel plant activators with thieno[2,3-d]-1,2,3-thiadiazole-6-carboxylate scaffold： Synthesis and bioactivity

The 1,2,3-thiadiazole-carboxylate moiety was reported to be an important pharmacophore of plant activators.In this study,a series of novel plant activators based on thieno[2,3-d]-1,2,3-thiadiazole-6-carboxylate were designed and synthesized and their biological activity as plant activators was studied.The structures of the novel compounds were identifed by1H NMR,19F NMR and HRMS.The in vivo bioassay showed that these novel compounds had good effcacy against seven plant diseases.Especially,compounds 1a and 1c were more potent than the commercialized plant activator BTH.Almost no fungicidal activity was observed for the active compounds in the in vitro assay,which matched the requirements as plant activators.     

Design,synthesis and biological evaluation of E-ring modified evodiamine derivatives as novel antitumor agents

A series of novel E-ring modified evodiamine derivatives were designed and synthesized as antitumor agents. Their capacity to interfere with the catalytic activity of topoisomerase Ⅰ and Ⅱ was evaluated by the relaxation assay. In vitro antitumor activity results revealed that compound 12 showed good antitumor activity with a broad spectrum. Its binding modes with topoisomerase Ⅰ and Ⅱ were clarified by molecular docking.     

Synthesis and biological evaluation of novel 1, 2, 3-benzotriazin-4-one derivatives as leukotriene A4 hydrolase aminopeptidase inhibitors

A series of novel 1,2,3-benzotriazin-4-one derivatives were designed,synthesized and their inhibitory activities against leulcotriene A_4 hydrolase aminopeptidase in vitro were evaluated.Many compounds showed moderate to good activities at the concentration of 10 μmol/L.Among them,compound Ⅳ-16 exhibited the highest inhibitory activity up to 80.6% with an IC_(50) of 1.30 ± 0.20 μmol/L The compound Ⅳ-16 was also tested the proliferation inhibitory activities in THP1 human AML cell line and its binding model with LTA_4H enzyme by molecular docking was studied.It indicated that 1,2,3-benzotriazin-4-one was a promising scaffold for further study.The relationship between structure and inhibitory activity was also preliminarily discussed.     

Synthesis and Herbicidal Activity of 3-Acetyl-4-hydroxy-2,1-benzothiazine Derivatives

In order to develop a novel herbicide containing the 2,1-benzothiazine motif, a series of 3-acetyl-4- hydroxy-2,1-benzothiazine derivatives was synthesized. All the target compounds were confirmed by 1H NMR,13C NMR, and high-resolution mass spectrometry(HRMS).In addition,the crystal structure of compoimd T27 was detemiined by single crystal X-ray diflraction. The bioassay results showed that some of the 3-acetyl-4-hydroxy- 2,1-benzothiazine derivatives(T13, T15, T22, and T24) showed good herbicidal activity at a dosage of 100 pg/mL. Among them,compounds T22 and T24 showed promising post-emergent herbicidal activities against Brassica campestris and Amaranthus retroflexus even at a dosage of 375 g/ha(1ha=104 m^2) in the greeiiliouse test. Studies on the structure-activity relationship demonstrated that the type of acetyl group played an important role in the herbicidal activity, and that the introduction of a phenoxyacetyl group at the 3-position of 2,1-beiizothiazine was beneficial in improving the herbicidal activity. The present study also indicated that 3-phenoxyacetyl-4-hydroxy-2,1-benzothiazine could be a potential lead compound for fiirther development of novel 2,1 -benzothiazine-containing herbicides.     

Synthesis,Characterization,Nematocidal Activity and Docking Study of Novel Pyrazole-4-carboxamide Derivatives

A series of novel 1-methyl-3-(trifluoromethyl)-~1H-pyrazole-4-carboxamide derivatives were designed based on our previous work and synthesized. All these title compounds were confirmed by NMR and MS. The primarily nematocidal activity results indicated that some of them exhibited good control efficacy against the tomato root-knot nematode disease caused by M. incognita. The docking results indicated that compound 6n interacts with amino acid residue Trp 279 of Ach E via hydrogen bond and amino acid residue Trp 84 of Ach E via π-π interaction.     

Synthesis and antibacterial activity of C-2(S)-substituted pleuromutilin derivatives

<正>In order to probe the effect of C-2(S)-substituted groups in the antibacterial activity,a series of novel C-2(S)-substituted pleuromutilin analogues of SB-225586 were synthesized and evaluated for their in vitro antibacterial activity.The results of antibacterial activities indicated that C-2(S)-substituted pleuromutilin derivatives retained appreciable antibacterial activity,and the 2-fluorination compounds 6a and 6b are more potent than the corresponding 2-hydroxylation analogues 7a and 7b.     

Synthesis, Crystal Structure and Biological Activities of O, O-Dialkyl α-[1-（2-Chlorothiazol-5-ylmethyl）-5-methyl- 1 H-1,2,3-triazol-4-ylcarbonyloxy]alkylphosphonates

In order to search for novel agrochemicals with high activity and low toxicity, a series of phosphonate derivatives containing 1,2,3-triazole and thiazole rings were designed and synthesized using 2-chloro-5-（chloromethyl）- thiazole as the starting material. Their structures were confirmed by IR, ^1H NMR, ^31p NMR, EI-MS or ESI-MS and elemental analyses. The crystal structure of 7a was determined by single crystal X-ray diffraction. Preliminary bioassays indicated that most of the target compounds did not display insecticidal activities, but a fraction of them possessed herbicidal and fungicidal activities to some extent.     

Synthesis,Bioactivity Evaluation,3D-QSAR,and Molecular Docking of Novel Pyrazole-4-carbohydrazides as Potential Fungicides Targeting Succinate Dehydrogenase

To screen novel antifungal agents targeting the succinate dehydrogenase(SDH),a series of pyrazole-4-carbohydrazides were rationally designed,synthesized,and characterized under the guidance of the structures of succinate dehydrogenase inhibitors(SDHIs).Bioassay results in vitro indicated that most of the target compounds exhibited excellent activity against Rhizoctonia solani(R.solani),Fusarium graminearum(F.graminearum),Botrytis cinerea(B.cinerea)and Colletotrichum capsica(C.cinerea).Compounds 7d,7l,7t and 7x were identified as the most promoting candidates,and their anti-F.graminearum EC50 values were as low as 0.56,0.47,0.46 and 0.49μg/mL,respectively,presenting the similar antifungal activity as that of the commonly used fungicide carbendazim(0.43μg/mL).The 3D-QSAR models were built for a systematic structure-activity relationship profile to explore more potent pyrazole-4-carbohydrazides as novel fungicides.Molecular docking of 7d,7l and 7r with SDH was performed to reveal the binding modes in active pocket and analyze the interactions between the molecules and the SDH protein.     

Synthesis and biological evaluation of nitric oxide-releasing sixalkoxyl biphenyl derivatives as anticancer agents

A series of novel nitric oxide-donating sixalkoxyl biphenyl derivatives （14a-1） were synthesized by coupling furoxan with alkoxyl biphenyl skeleton using amino acids as the spacers, and their cytotoxicity against HepG2 cells in vitro were evaluated by MTT method. It was found that 14c, 14d, 14f, 14i, 14j and 14k showed more potent cytotoxic activities than control 5-fluorouracil. NO release assay of target compounds indicated that the maximum amount of NO released by most active compounds 14c and 14j was about 6 × 10^-2 μmol/L, whereas 14a and 14h with very weak activity only released NO of 1 × 10^-2 μmol/L.     

Novel pyrazole fused heterocyclic ligands: Synthesis,characterization, DNA binding/cleavage activity and anti-BVDV activity

A series of novel pyrazole fused heterocyclic derivatives were synthesized via a two-step procedure or a one-pot two step method,and their catalytic DNA cleavage abilities and anti-BVDV activities were also evaluated.The results obtained indicated that compounds 3b-3c could catalyze the cleavage of supercoiled DNA(pUC 19 plasmid DNA) to nicked DNA under physiological conditions with high yields via a hydroiytic mechanism.The studies on anti-viral activities against bovine viral diarrhea virus(BVDV) demonstrated that some of the pyrazole derivatives showed pronounced anti-BVDV activity with interesting EC_(50) values and no significant cytotoxicity.Among them,compound 31 showed the highest antiviral activity(EC_(50) = 0.12 μmoI/L) and was 10 fold more than that of the positive control ribavirin(EC_(50)= 1.3 μmol/L),which provided a potential candidate for the development of anti-BVDV agents.     

A Novel β-1, 4-N, 6-O-Diacetylmuramidase from Streptomyces griseus and its Chemical Modification

A novel lysozyme namedβ-1, 4-N, 6-O-diacetylmuramidase R2 was purified and characterized from Streptomyces griseus. The molecular weight of the enzyme was determined by MALDI-TOF-MS as 23.5 kDa. The N-terminal amino acid sequence was DTSGVQGIDVS-HWQG.Chemical modification ofβ-1, 4-N, 6-O-diacetylmuramidase R2 indicated that sulfhydry1 group and carbamidine of arginine residues are not essential for the activity of the enzyme, but lysine residues and imidazole of histidine residues are essential for the activity. The number of essential tryptophan and carboxyl groups was found that only one tryptophan residue and three carboxyl groups in the active site.     

Asymmetric Synthesis, Antifungal Activity and Molecular Modeling of Iodiconazole Isomers

Iodiconazole is a novel antifungal agent that was developed in its racemic form. In order to investigate the ef- fects of the chiral center on the antifungal activity, R- and S-isomers of iodiconazole were prepared on the basis of the asymmetric Sharpless epoxidation. （S）-Iodiconazole was proved to have better antifungal activity than the （R）- isomer. The binding modes of the two isomers with lanosterol 14~z-demethylase were clarified by molecular dock- ing.