Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibi...Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.展开更多
The structure, properties and application to water-soluble coatings of a new complex antimicrobial agent Ag-carboxylmethyl citosan-thiabendazole （Ag-CMCTS-TBZ） prepared from different materiel ratios were reported. ...The structure, properties and application to water-soluble coatings of a new complex antimicrobial agent Ag-carboxylmethyl citosan-thiabendazole （Ag-CMCTS-TBZ） prepared from different materiel ratios were reported. The silver ions were preferably coordinated with the free-NH2 groups and the -OH groups of secondary alcohol and carboxyl in CMCTS. TBZ preferably bonded to carboxyl group in CMCTS by electrostatic force and hydrogen bonding. Increase in silver ions content in the complex agent improved to some limited extent the antibacterial activity, but enhanced coloring and cost of the complex agent. Increase in TBZ content resulted in increase of antifungal activity, but decrease of water solubility of the complex agent. The antimicrobial MICs of the complex agent to Esherichia coil, Staphylococcus aureus, Candida albicans, Aspergillus niger, Mucor sp. were 20 -80, 15 -60, 20 - 55, 40 - 250, and 400 - 1700 mg/kg, respectively. Addition of 0.1% of this complex agent to acrylic emulsion paint made the paint without substantial change in color, luster, viscosity, odor or pH value, but with an excellent and chronically persisting broad-spectra antimicrobial activity.展开更多
The intermediate of d-biotin, (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4- d]-imidazole-2(3H)-one-4-ylidenepentanoil acid was synthesized from (3aS,6aR)-1,3-dibenzylte- trahyro-4H-thieno[3,4-d]-imidazole-2,4(1H)-di...The intermediate of d-biotin, (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4- d]-imidazole-2(3H)-one-4-ylidenepentanoil acid was synthesized from (3aS,6aR)-1,3-dibenzylte- trahyro-4H-thieno[3,4-d]-imidazole-2,4(1H)-dione by using the Grignard reaction. The structure of 3 was characterized by IR, 1H NMR and MS, and the absolute configuration was further confirmed by X-ray crystal structure analysis. Compound 3 crystallizes in monoclinic, space group P21 with a = 11.030(2), b = 7.783(2), c = 12.797(2) , b = 93.44(1)o, Z = 2, Mr = 422.53 (C24H26N2O3S), V = 1096.3(6) 3, = 0.177 mm-1, Dc = 1.280 g/cm3, F(000) = 448 and T = 293(2) K. The final R = 0.0737 and Rw = 0.1974 for 1009 observed reflections with I >2s(I).展开更多
文摘Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.
文摘The structure, properties and application to water-soluble coatings of a new complex antimicrobial agent Ag-carboxylmethyl citosan-thiabendazole （Ag-CMCTS-TBZ） prepared from different materiel ratios were reported. The silver ions were preferably coordinated with the free-NH2 groups and the -OH groups of secondary alcohol and carboxyl in CMCTS. TBZ preferably bonded to carboxyl group in CMCTS by electrostatic force and hydrogen bonding. Increase in silver ions content in the complex agent improved to some limited extent the antibacterial activity, but enhanced coloring and cost of the complex agent. Increase in TBZ content resulted in increase of antifungal activity, but decrease of water solubility of the complex agent. The antimicrobial MICs of the complex agent to Esherichia coil, Staphylococcus aureus, Candida albicans, Aspergillus niger, Mucor sp. were 20 -80, 15 -60, 20 - 55, 40 - 250, and 400 - 1700 mg/kg, respectively. Addition of 0.1% of this complex agent to acrylic emulsion paint made the paint without substantial change in color, luster, viscosity, odor or pH value, but with an excellent and chronically persisting broad-spectra antimicrobial activity.
基金a Grant-in-Aid (96107) for Scientific Research from the Ministry of Chemical Industry of China
文摘The intermediate of d-biotin, (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4- d]-imidazole-2(3H)-one-4-ylidenepentanoil acid was synthesized from (3aS,6aR)-1,3-dibenzylte- trahyro-4H-thieno[3,4-d]-imidazole-2,4(1H)-dione by using the Grignard reaction. The structure of 3 was characterized by IR, 1H NMR and MS, and the absolute configuration was further confirmed by X-ray crystal structure analysis. Compound 3 crystallizes in monoclinic, space group P21 with a = 11.030(2), b = 7.783(2), c = 12.797(2) , b = 93.44(1)o, Z = 2, Mr = 422.53 (C24H26N2O3S), V = 1096.3(6) 3, = 0.177 mm-1, Dc = 1.280 g/cm3, F(000) = 448 and T = 293(2) K. The final R = 0.0737 and Rw = 0.1974 for 1009 observed reflections with I >2s(I).
