N,N-Bis(2-pyridylmethyl)-amine-N-ethyl-2-pyridine-2-carboxamide was synthesized and characterized according to the literature. At 25 ℃, I=0.1 mol/L KNO 3, the stability constants of the binary system formed by the li...N,N-Bis(2-pyridylmethyl)-amine-N-ethyl-2-pyridine-2-carboxamide was synthesized and characterized according to the literature. At 25 ℃, I=0.1 mol/L KNO 3, the stability constants of the binary system formed by the ligand with metal ions in ethanol aqueous solution were studied by pH potentiometric titration and the appropriate structures with respect to the titration species were proposed. The results show that the stability order of divalent metals binding to the ligand is Co<Ni>Cu<Zn which does not conform to the order of the Irving-Williams series. Then the abnormal property of copper complex is discussed.展开更多
Pyrazole carboxamide derivatives represent an important class of fungicides in agrochemicals. To find more novel structural pyrazole carboxamides, a novel series of 3-（trifluoromethyl）-lH-pyrazole-4-carboxamide comp...Pyrazole carboxamide derivatives represent an important class of fungicides in agrochemicals. To find more novel structural pyrazole carboxamides, a novel series of 3-（trifluoromethyl）-lH-pyrazole-4-carboxamide compounds were prepared from ethyl 4,4,4-trifluoroace- toacetate and triethyl orthoformate as starting materials. All the products were characterized by Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance （NMR）, 13C NMR, 19F NMR and mass spectrography. The bioassay results showed these fluorine-containing pyrazole carboxamides have a weak fungicidal activity but some of them exhibit a good nematocidal activity against M. incognita.展开更多
A series of(R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety were synthesized and characterized on the basis of NMR and elemental analysis(EA). The crystal structure of(R)-N-(...A series of(R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety were synthesized and characterized on the basis of NMR and elemental analysis(EA). The crystal structure of(R)-N-(2-methyl-1-(methylthio)propan-2-yl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carboxamide(13 d) was determined to show R configuration. The bioasssy results indicated that most title compounds displayed good and broad spectrum antifungal activities against several phytopathogenic fungi. The structure activity relationships were discussed. Based on the antifungal activity of title compounds against Phytophthora capsici, a CoMSIA calculation was performed to establish a 3 D-QSAR model, which revealed that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. According to the established 3D-QSAR model, structure optimization was carried out to find(R)-N-((R)-1-(methylthio)propan-2-yl)-2-(p-tolyl)-4,5-dihydrothiazole-4-carboxamide(15 h)with excellent activity against Phytophthora capsici, thus emerging as a new lead compound for novel antiphytopathogenic fungus agent development.展开更多
In order to discover new molecules with good insecticidal activities, a series of anthranilic diamides containing polyfluoroalkyl pyrazole were designed and synthesized, and their structures were characterized by1 H N...In order to discover new molecules with good insecticidal activities, a series of anthranilic diamides containing polyfluoroalkyl pyrazole were designed and synthesized, and their structures were characterized by1 H NMR and HRMS. Bioassays demonstrated that some of the title compound exhibited excellent insecticidal activities. The larvicidal activities of compound 8a, 8c, 8g, 8k and 8l against Mythimna separata Walker were 100% at 0.8 mg/L. The insecticidal activities of compound 8a, 8c,8e, 8g, 8k and 8l against Plutella xylostella Linnaeus were 100% at 0.4 mg/L. Surprisingly compounds 8a and 8c still showed 100% larvicidal activities against Plutella xylostella Linnaeus at 0.08 mg/L comparable to the commercialized Chlorantraniliprole. The LC_（50） of compound 8a and 8c against M. separata is 0.048 and 0.043 mg/L respectively.展开更多
Twenty-seven novel pyrazole carboxamides with diarylamine-modified scaffold were designed,synthesized and characterized in detail via1 H NMR,^（13） C NMR, IR and ESI-HRMS. Preliminary bioassays showed that some of th...Twenty-seven novel pyrazole carboxamides with diarylamine-modified scaffold were designed,synthesized and characterized in detail via1 H NMR,^（13） C NMR, IR and ESI-HRMS. Preliminary bioassays showed that some of the target compounds exhibited good antifungal activity against Rhizoctonia solani,Rhizoctonia cerealis and Sclerotinia sclerotiorum. Among them, compound 9c-7 exhibited the highest antifungal activities against R. solani, R. cerealis and S. sclerotiorum in vitro with IC_（50） values of 0.013, 1.608 and 1.874 mg/m L, respectively. Notably, compound 9c-7 still presented the highest fungicidal activities against R. solani in vivo with an IC_（50） value of 22.21 mg/m L. Molecular docking simulation results reveal that compound 9c-7 binds well to the hydrophobic pockets of the receptor protein succinate dehydrogenase. This study suggests that compound 9c-7 could act as a potential fungicide to be used for further optimization.展开更多
The crystal structure of the title compound （C12H10ClN7OS, Mr= 335.78） has been determined by single-crystal X-ray diffraction. The crystal is of triclinic, space group Pi with a = 8.4093（11）, b = 9.4430（12）, c ...The crystal structure of the title compound （C12H10ClN7OS, Mr= 335.78） has been determined by single-crystal X-ray diffraction. The crystal is of triclinic, space group Pi with a = 8.4093（11）, b = 9.4430（12）, c = 11.1454（14） A, α = 95.508（2）, β = 111.366（2）, γ = 115.259（2）°, V = 711.42（16） A3, Z = 2, Dc = 1.568 g/cm3, F（000） = 344, μ（MoKα） = 0.428 mm-1, the final R = 0.0476 and wR = 0.1243 for 2353 observed reflections （I 〉 2o（/））. The dihedral angles between the pyridine and triazole, thiazole and triazole, and pyridine and thiazole rings are 69.2（1）, 9.2（1） and 72.7（1）°, respectively. Intramolecular C（8）--H（8B）...O（1） and N（5）-H（5A）..-N（4） as well as intermolecular C（5）-H（5）...S（1）, C（3）-H（3）.,.N（6） and N（5）-H（5A）...N（1） hydrogen bonds together with weak C-H...Ir hydrogen-bonding and π-π stacking interactions contribute to the stability of the structure. There is also evidence for significant electron delocalization in the triazolyl system.展开更多
a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent yea...a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent years.In this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions.Notably,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL signaling.In turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar level.More importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL inhibitor.Taken together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.展开更多
为寻找新型结构的琥珀酸脱氢酶抑制剂,以高效杀菌剂啶酰菌胺为先导化合物,设计、合成了17种N-[2-((取代苯基)氨基)吡啶-3-基]-4-甲基-2-甲硫基嘧啶-5-甲酰胺(4a^4g)和N-[2-((取代苯基)氨基)吡啶-3-基]-4-甲氧基-2-甲硫基嘧啶-5-甲酰胺(4...为寻找新型结构的琥珀酸脱氢酶抑制剂,以高效杀菌剂啶酰菌胺为先导化合物,设计、合成了17种N-[2-((取代苯基)氨基)吡啶-3-基]-4-甲基-2-甲硫基嘧啶-5-甲酰胺(4a^4g)和N-[2-((取代苯基)氨基)吡啶-3-基]-4-甲氧基-2-甲硫基嘧啶-5-甲酰胺(4h^4q),并通过1 H NMR、13C NMR和MALDI-TOF-MS确证了化合物的结构.离体杀菌活性试验表明,在剂量为50μg/mL时,16种化合物对菌核菌表现出较高的杀菌活性,抑制率在90%以上.一些化合物在此剂量下对灰霉菌显示出中等活性,抑制率为70%~84%.分子对接研究揭示了具有较高活性的化合物,N-[2-((3-氟-4-甲基苯基)氨基)吡啶-3-基]-2-甲硫基-4-甲氧基嘧啶-5-甲酰胺(4p)与琥珀酸脱氢酶(SDH)靶酶氨基酸形成4个氢键和一个阳离子-π相互作用.展开更多
We have synthesized a series of compounds based on a piperidyl benzimidazole carboxamide structure,and tested their PARP-1 inhibitory activity,as well as cellular inhibitory activity.Some of them show great potency as...We have synthesized a series of compounds based on a piperidyl benzimidazole carboxamide structure,and tested their PARP-1 inhibitory activity,as well as cellular inhibitory activity.Some of them show great potency as PARP-1 inhibitors and antitumor activity,which are valuable for further research.In addition,the predicted ADME properties and proposed binding mode with PARP-1 of the compounds were obtained via computational simulation.展开更多
Inactivation of Glucokinase (GK) is associated with diabetes. Therefore, design of drugs targeting the GK activator site is currently integrated in the?strategy of the diabetes treatment.?The present work investigated...Inactivation of Glucokinase (GK) is associated with diabetes. Therefore, design of drugs targeting the GK activator site is currently integrated in the?strategy of the diabetes treatment.?The present work investigated the affinity of 30 ligands to GK based on molecular docking using the Gold 5.6 program. Glucokinase’s structure was derived from the Protein Data Bank (PDB Code?3S41), while the ligands were seleno, sulfo and oxo derivatives of the co-crystallized?carboxamide activator (PDB code:?S41). The results of the ligand-protein docking?revealed that GK formed thermodynamically stable complexes with all ligands. The main forces stabilizing the complexes are lipophilic interactions, enhanced by hydrogen bonds. Ligand molecular areas responsible for lipophilic and hydrogen bonding contacts with amino acid residues in the allosteric site of GK were evidenced by molecular electrostatic potentials (MEPs). Interestingly,?twelve of the S41 derivatives interacted with GK more strongly than the co-crystallized activator, while maintaining the lipophilic contacts with key amino acid residues like Arg63, which are catalytically crucial for?therapeutic properties of GK activators (GKAs).?It is noteworthy that divalent Se and S atoms were also involved in chalcogen bonds in the GKA site. Those bonds were nearly linear like hydrogen bonds. Such bond directionality should guide the design of pharmacophoric ligands containing chalcogen atoms.展开更多
The synthesis of the title molecule was achieved by the reaction of 2,4-dichloro- benzoyl chloride with potassium thiocyanate in 1：1 molar ratio in dry acetonitrile to afford the corresponding isothiocyante in situ f...The synthesis of the title molecule was achieved by the reaction of 2,4-dichloro- benzoyl chloride with potassium thiocyanate in 1：1 molar ratio in dry acetonitrile to afford the corresponding isothiocyante in situ followed by the treatment with 2-aminobiphenyl. The structure of the target compound was established by elemental analysis, FTIR, 1H, 13C NMR and mass spectroscopy and unequivocally confirmed by the crystallographic data. The title compound crystallizes in the monoclinic space group P21/n with a = 13.356（2）, b = 7.0761（11）, c = 20.539（3） A, β = 105.723（4）°, V= 1868.5（5） A3 and Z = 4.展开更多
A series of novel furan-1,3,4-oxadiazole carboxamide derivatives (5a~5e) were designed,synthesized and characterized by spectroscopic methods including HR-MS,^(1)H-and ^(13)C-NMR.The crystal structure of compound 5a w...A series of novel furan-1,3,4-oxadiazole carboxamide derivatives (5a~5e) were designed,synthesized and characterized by spectroscopic methods including HR-MS,^(1)H-and ^(13)C-NMR.The crystal structure of compound 5a was determined by single-crystal X-ray diffraction.The compound crystallizes in the triclinic system,space group P■ with a=4.7261(5),b=10.4672(11),c=14.5886(13)?,α=106.081(4)°,β=91.043(3)°,γ=99.456(4)°,Z=2,V=682.48(12)?^(3),M_(r)=348.16,D_(c)=1.694 Mg/m^(3),S=1.008,m=3.025 mm^(-1),F(000)=348,the final R=0.0775 and w R=0.2080 for 2774 observed reflections (I (29) 2σ(I)).There are two kinds of hydrogen bonds (N(3)–H(3A)×××N(2) and C(8)–H(8A)×××O(3)) present in its crystal structure.The preliminary antifungal assay showed that compounds 5b and 5c exhibited significant antifungal activities against several plant pathogenic fungi.展开更多
In this paper, 42 4-hydroxyamino α-pyranone carboxamide analogues as Hepatitis C Virus(HCV) inhibitor 3 D-QSAR model was built based on Topomer CoMFA. The non-cross-validation(r2), cross-validation(q2), correlation c...In this paper, 42 4-hydroxyamino α-pyranone carboxamide analogues as Hepatitis C Virus(HCV) inhibitor 3 D-QSAR model was built based on Topomer CoMFA. The non-cross-validation(r2), cross-validation(q2), correlation coefficient of external validation(Q ext2), non-cross validated standard error(SD), standard error of prediction(SDCV) and F are 0.909, 0.615, 0.967, 0.13, 0.28 and 37.287, respectively. The obtained Topomer CoMFA model has good estimation stability and prediction capability. Topomer Search was employed as a tool for virtual screening in lead-like compounds in the ZINC database. Then, 6 R1 groups and 4 R2 groups with higher contribution values were employed to alternately substitute for the R1 and R2 of the template compound 21 with the highest bioactivity. As a result, 22 new molecules with higher activity than that of the template molecule were designed successfully. The Topomer Search technology could be effectively applied to screen and design new 4-hydroxyamino α-pyranone carboxamide analogues. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HCV active site, which revealed the likely bioactive conformations. This study showed extensive interactions between the 4-hydroxyamino α-pyranone carboxamide analogues and the active sites of HCV(residues TYR466, GLN384, TYR383 and ASP335). The design of potent new inhibitors of HCV can get useful insights from these results.展开更多
文摘N,N-Bis(2-pyridylmethyl)-amine-N-ethyl-2-pyridine-2-carboxamide was synthesized and characterized according to the literature. At 25 ℃, I=0.1 mol/L KNO 3, the stability constants of the binary system formed by the ligand with metal ions in ethanol aqueous solution were studied by pH potentiometric titration and the appropriate structures with respect to the titration species were proposed. The results show that the stability order of divalent metals binding to the ligand is Co<Ni>Cu<Zn which does not conform to the order of the Irving-Williams series. Then the abnormal property of copper complex is discussed.
文摘Pyrazole carboxamide derivatives represent an important class of fungicides in agrochemicals. To find more novel structural pyrazole carboxamides, a novel series of 3-（trifluoromethyl）-lH-pyrazole-4-carboxamide compounds were prepared from ethyl 4,4,4-trifluoroace- toacetate and triethyl orthoformate as starting materials. All the products were characterized by Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance （NMR）, 13C NMR, 19F NMR and mass spectrography. The bioassay results showed these fluorine-containing pyrazole carboxamides have a weak fungicidal activity but some of them exhibit a good nematocidal activity against M. incognita.
基金financially supported by the Scientific Project of Tianjin Municipal Education Commission(No. 2018KJ008)Tianjin Natural Science Foundation(No. 16JCYBJC29400)
文摘A series of(R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety were synthesized and characterized on the basis of NMR and elemental analysis(EA). The crystal structure of(R)-N-(2-methyl-1-(methylthio)propan-2-yl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carboxamide(13 d) was determined to show R configuration. The bioasssy results indicated that most title compounds displayed good and broad spectrum antifungal activities against several phytopathogenic fungi. The structure activity relationships were discussed. Based on the antifungal activity of title compounds against Phytophthora capsici, a CoMSIA calculation was performed to establish a 3 D-QSAR model, which revealed that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. According to the established 3D-QSAR model, structure optimization was carried out to find(R)-N-((R)-1-(methylthio)propan-2-yl)-2-(p-tolyl)-4,5-dihydrothiazole-4-carboxamide(15 h)with excellent activity against Phytophthora capsici, thus emerging as a new lead compound for novel antiphytopathogenic fungus agent development.
基金supported by Key Projects of the National Science and Technology Pillar Program of China(No.2011BAE06B01-20)
文摘In order to discover new molecules with good insecticidal activities, a series of anthranilic diamides containing polyfluoroalkyl pyrazole were designed and synthesized, and their structures were characterized by1 H NMR and HRMS. Bioassays demonstrated that some of the title compound exhibited excellent insecticidal activities. The larvicidal activities of compound 8a, 8c, 8g, 8k and 8l against Mythimna separata Walker were 100% at 0.8 mg/L. The insecticidal activities of compound 8a, 8c,8e, 8g, 8k and 8l against Plutella xylostella Linnaeus were 100% at 0.4 mg/L. Surprisingly compounds 8a and 8c still showed 100% larvicidal activities against Plutella xylostella Linnaeus at 0.08 mg/L comparable to the commercialized Chlorantraniliprole. The LC_（50） of compound 8a and 8c against M. separata is 0.048 and 0.043 mg/L respectively.
基金supported by National Key Research and Development Program of China(No.2016YFC0502004-2)Applied Basic Research Program of Sichuan Province(No.2014JY0063)
文摘Twenty-seven novel pyrazole carboxamides with diarylamine-modified scaffold were designed,synthesized and characterized in detail via1 H NMR,^（13） C NMR, IR and ESI-HRMS. Preliminary bioassays showed that some of the target compounds exhibited good antifungal activity against Rhizoctonia solani,Rhizoctonia cerealis and Sclerotinia sclerotiorum. Among them, compound 9c-7 exhibited the highest antifungal activities against R. solani, R. cerealis and S. sclerotiorum in vitro with IC_（50） values of 0.013, 1.608 and 1.874 mg/m L, respectively. Notably, compound 9c-7 still presented the highest fungicidal activities against R. solani in vivo with an IC_（50） value of 22.21 mg/m L. Molecular docking simulation results reveal that compound 9c-7 binds well to the hydrophobic pockets of the receptor protein succinate dehydrogenase. This study suggests that compound 9c-7 could act as a potential fungicide to be used for further optimization.
基金supported by NNSFC (20302002)the Foundation for the Returned Overseas Chinese Scholars (No. [2007] 1108)
文摘The crystal structure of the title compound （C12H10ClN7OS, Mr= 335.78） has been determined by single-crystal X-ray diffraction. The crystal is of triclinic, space group Pi with a = 8.4093（11）, b = 9.4430（12）, c = 11.1454（14） A, α = 95.508（2）, β = 111.366（2）, γ = 115.259（2）°, V = 711.42（16） A3, Z = 2, Dc = 1.568 g/cm3, F（000） = 344, μ（MoKα） = 0.428 mm-1, the final R = 0.0476 and wR = 0.1243 for 2353 observed reflections （I 〉 2o（/））. The dihedral angles between the pyridine and triazole, thiazole and triazole, and pyridine and thiazole rings are 69.2（1）, 9.2（1） and 72.7（1）°, respectively. Intramolecular C（8）--H（8B）...O（1） and N（5）-H（5A）..-N（4） as well as intermolecular C（5）-H（5）...S（1）, C（3）-H（3）.,.N（6） and N（5）-H（5A）...N（1） hydrogen bonds together with weak C-H...Ir hydrogen-bonding and π-π stacking interactions contribute to the stability of the structure. There is also evidence for significant electron delocalization in the triazolyl system.
基金supported by the Natural Science Foundation of China for Innovation Research Group(81821005)the National Natural Science Foundation of China(21977106 and 82173834)+4 种基金the Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning(2020CXJQ02)the Shanghai Post-doctoral Excellence Program(2022231,China)the Shanghai Sail Program(22YF1460700,China)Lingang Laboratory(LG202103-02-07,China)Lingang Laboratory(LGGG-202204-02,China).
文摘a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent years.In this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions.Notably,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL signaling.In turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar level.More importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL inhibitor.Taken together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.
文摘为寻找新型结构的琥珀酸脱氢酶抑制剂,以高效杀菌剂啶酰菌胺为先导化合物,设计、合成了17种N-[2-((取代苯基)氨基)吡啶-3-基]-4-甲基-2-甲硫基嘧啶-5-甲酰胺(4a^4g)和N-[2-((取代苯基)氨基)吡啶-3-基]-4-甲氧基-2-甲硫基嘧啶-5-甲酰胺(4h^4q),并通过1 H NMR、13C NMR和MALDI-TOF-MS确证了化合物的结构.离体杀菌活性试验表明,在剂量为50μg/mL时,16种化合物对菌核菌表现出较高的杀菌活性,抑制率在90%以上.一些化合物在此剂量下对灰霉菌显示出中等活性,抑制率为70%~84%.分子对接研究揭示了具有较高活性的化合物,N-[2-((3-氟-4-甲基苯基)氨基)吡啶-3-基]-2-甲硫基-4-甲氧基嘧啶-5-甲酰胺(4p)与琥珀酸脱氢酶(SDH)靶酶氨基酸形成4个氢键和一个阳离子-π相互作用.
基金Shenzhen Sci.& Tech.Bureau (Nos.JCYJ20170816170342439 and JCYJ20170413113448742) for the financial supports
文摘We have synthesized a series of compounds based on a piperidyl benzimidazole carboxamide structure,and tested their PARP-1 inhibitory activity,as well as cellular inhibitory activity.Some of them show great potency as PARP-1 inhibitors and antitumor activity,which are valuable for further research.In addition,the predicted ADME properties and proposed binding mode with PARP-1 of the compounds were obtained via computational simulation.
文摘Inactivation of Glucokinase (GK) is associated with diabetes. Therefore, design of drugs targeting the GK activator site is currently integrated in the?strategy of the diabetes treatment.?The present work investigated the affinity of 30 ligands to GK based on molecular docking using the Gold 5.6 program. Glucokinase’s structure was derived from the Protein Data Bank (PDB Code?3S41), while the ligands were seleno, sulfo and oxo derivatives of the co-crystallized?carboxamide activator (PDB code:?S41). The results of the ligand-protein docking?revealed that GK formed thermodynamically stable complexes with all ligands. The main forces stabilizing the complexes are lipophilic interactions, enhanced by hydrogen bonds. Ligand molecular areas responsible for lipophilic and hydrogen bonding contacts with amino acid residues in the allosteric site of GK were evidenced by molecular electrostatic potentials (MEPs). Interestingly,?twelve of the S41 derivatives interacted with GK more strongly than the co-crystallized activator, while maintaining the lipophilic contacts with key amino acid residues like Arg63, which are catalytically crucial for?therapeutic properties of GK activators (GKAs).?It is noteworthy that divalent Se and S atoms were also involved in chalcogen bonds in the GKA site. Those bonds were nearly linear like hydrogen bonds. Such bond directionality should guide the design of pharmacophoric ligands containing chalcogen atoms.
文摘The synthesis of the title molecule was achieved by the reaction of 2,4-dichloro- benzoyl chloride with potassium thiocyanate in 1：1 molar ratio in dry acetonitrile to afford the corresponding isothiocyante in situ followed by the treatment with 2-aminobiphenyl. The structure of the target compound was established by elemental analysis, FTIR, 1H, 13C NMR and mass spectroscopy and unequivocally confirmed by the crystallographic data. The title compound crystallizes in the monoclinic space group P21/n with a = 13.356（2）, b = 7.0761（11）, c = 20.539（3） A, β = 105.723（4）°, V= 1868.5（5） A3 and Z = 4.
基金supported by the National Natural Science Foundation of China (31770616)the Natural Science Foundation for Colleges and Universities in Jiangsu Province (17KJA220002)。
文摘A series of novel furan-1,3,4-oxadiazole carboxamide derivatives (5a~5e) were designed,synthesized and characterized by spectroscopic methods including HR-MS,^(1)H-and ^(13)C-NMR.The crystal structure of compound 5a was determined by single-crystal X-ray diffraction.The compound crystallizes in the triclinic system,space group P■ with a=4.7261(5),b=10.4672(11),c=14.5886(13)?,α=106.081(4)°,β=91.043(3)°,γ=99.456(4)°,Z=2,V=682.48(12)?^(3),M_(r)=348.16,D_(c)=1.694 Mg/m^(3),S=1.008,m=3.025 mm^(-1),F(000)=348,the final R=0.0775 and w R=0.2080 for 2774 observed reflections (I (29) 2σ(I)).There are two kinds of hydrogen bonds (N(3)–H(3A)×××N(2) and C(8)–H(8A)×××O(3)) present in its crystal structure.The preliminary antifungal assay showed that compounds 5b and 5c exhibited significant antifungal activities against several plant pathogenic fungi.
基金supported by the National Natural Science Foundation of China (21475081)the Natural Science Foundation of Shaanxi Province (2019JM-237)the Graduate Innovation Fund of Shaanxi University of Science and Technology。
文摘In this paper, 42 4-hydroxyamino α-pyranone carboxamide analogues as Hepatitis C Virus(HCV) inhibitor 3 D-QSAR model was built based on Topomer CoMFA. The non-cross-validation(r2), cross-validation(q2), correlation coefficient of external validation(Q ext2), non-cross validated standard error(SD), standard error of prediction(SDCV) and F are 0.909, 0.615, 0.967, 0.13, 0.28 and 37.287, respectively. The obtained Topomer CoMFA model has good estimation stability and prediction capability. Topomer Search was employed as a tool for virtual screening in lead-like compounds in the ZINC database. Then, 6 R1 groups and 4 R2 groups with higher contribution values were employed to alternately substitute for the R1 and R2 of the template compound 21 with the highest bioactivity. As a result, 22 new molecules with higher activity than that of the template molecule were designed successfully. The Topomer Search technology could be effectively applied to screen and design new 4-hydroxyamino α-pyranone carboxamide analogues. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HCV active site, which revealed the likely bioactive conformations. This study showed extensive interactions between the 4-hydroxyamino α-pyranone carboxamide analogues and the active sites of HCV(residues TYR466, GLN384, TYR383 and ASP335). The design of potent new inhibitors of HCV can get useful insights from these results.
