Integrase（IN） plays an essential role in the process of HIV-1 replication.IN inhibitors of diketo acid derivatives（DKAs） were analysed by the Comparative Molecular Field Analysis（CoMFA） and Comparative Molecular...Integrase（IN） plays an essential role in the process of HIV-1 replication.IN inhibitors of diketo acid derivatives（DKAs） were analysed by the Comparative Molecular Field Analysis（CoMFA） and Comparative Molecular Similarity Induces Analysis（CoMSIA） methods.A set of 42 compounds were randomly selected as the training set（35） and test set（7）.Firstly,a good pharmacophore（goodness of hit=0.787） was obtained and used to align ligands.Then,predictive models were constructed with the CoMFA and CoMSIA methods based on the pharmacophore alignment.As a result,the CoMS1A method yielded the best model with an r2 of 0.955 and a q2 of 0.665,which can predict the activities of the tested DKAs very well（r2=0.559）.Finally,DKAs were docked into IN,and the predicit modes were superimposed on the contour maps obtained from the best CoMSIA model.The superimposed maps gave a visualized and meaningful insight into the inhibitory behaviors,providing significantly useful information for the rational drug design of anti-IN agents.展开更多
Aryl diketo acid derivatives are one of the most promising HIV-1 integrase（IN） inhibitors. With a view to substitute the critical diketo acid pharmacophore with the diketo benzimidazole unit, the coupling reaction o...Aryl diketo acid derivatives are one of the most promising HIV-1 integrase（IN） inhibitors. With a view to substitute the critical diketo acid pharmacophore with the diketo benzimidazole unit, the coupling reaction of compound 4 with o-phenylenediamine was carried out. However, the reaction product, compound 5, was confirmed to be 3-{ [ 3- （phenylsulfonamido） benzoyl] methylidene t -3,4-dihydroquinoxaline-2 （1H） -one rather than the 2-benzimidazole derivative by using X-ray diffraction. Owing to its low solubility in water, the evaluation of the anti-HIV IN activity of the synthesized compound 5 could not be carried out. Consequently, the ion-binding properties of compound 5 in the absence of HIV-1 IN were investigated with UV-Vis spectroscopy in organic solvents. The results show that such a compound can selectively recognize Cu^2＋.展开更多
As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HI...As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HIV-1 IN. In the present work, two three-dimensional QSAR techniques （CoMFA and CoMSIA） were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search （AOS） and all-placement search （APS） were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the HIV-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent HIV-1 integrase inhibitors.展开更多
The study dealed with quantitative structure-activity relationship(QSAR)to explore the important features of diketo acid(DKA)derivatives for exerting potent HIV-1 integrase inhibitors activity.A three-step screening m...The study dealed with quantitative structure-activity relationship(QSAR)to explore the important features of diketo acid(DKA)derivatives for exerting potent HIV-1 integrase inhibitors activity.A three-step screening method was proposed to choose descriptors.Then,additional descriptors were used in the CoMFA and CoMSIA.Lastly,a modified CoMSIA m7 model,constructed by adding Csp^2_03_F descriptor,showed better predictive ability.Validation parameters(Q^2 and R^2)for the models were 0.722 and 0.925,respectively.In addition,external validation for the models using a test group revealed R^2pred=0.892.Contour maps analysis defined favored and disfavored regions of the compounds,and two new compounds with the descriptor structure were designed with better activities than Raltegravir(RAL),well drug-likeness and low toxicity.The research provides a base for further DKA development.展开更多
The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 1...The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 19.434（5） A, β = 104.411（4）°, Mr = 804.85, Dc = 1.288 g/cm3, V = 4149.2（17） A3, Z = 4, F（000） = 1696, #（MoKa） = 0.089 mm-1T = 296（2） K, 7279 independent reflections with 3172 observed ones （I 〉 2δ（/））, R = 0.0520 and wR = 0.1203 with GOF = 0.928 （R = 0.1464 and wR = 0.1657 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O-H…O hydrogen bonds. Preliminary bioassays indicated that the title compound has a potent inhibitory activity against the strand transfer process of HIV-1 integrase.展开更多
Diketo acid derivatives are potent and selective HIV-1 integrase inhibitors. To investigate the detailed synthesis of those derivatives, a series of p/m-[p-（un）substituted phenylsulfonamido]phenyl β-diketo acid der...Diketo acid derivatives are potent and selective HIV-1 integrase inhibitors. To investigate the detailed synthesis of those derivatives, a series of p/m-[p-（un）substituted phenylsulfonamido]phenyl β-diketo acid derivatives have been designed and synthesized. The quinoxalone derivatives as the potential bioisosteres of the biologically labile β-diketoacid pharmacophores have also been synthesized from reactions of the corresponding diketo acids with o-phenylenediamine. The structures of all diketo acid （ester） and quinoxalone derivatives were confirmed by 1^H NMR, 13^C NMR, IR, HRMS and/or MS （ESI）. X-ray crystallographic analysis of 11b demonstrates a similar arrangement of the side chain of quinoxalone derivatives with the parent diketoacids due to the intramolecular hydrogen bond （O…H-N） and the sp^2 hybridization configuration of the two nitrogen atoms of the quinoxalone ring.展开更多
A series of novel calix[4]arene derivatives incorporating two triazolyl 1 3-diketo subunits in alternate positions at the lower rim were synthesized and screened for HⅣ integrase inhibition activity.The chemical stru...A series of novel calix[4]arene derivatives incorporating two triazolyl 1 3-diketo subunits in alternate positions at the lower rim were synthesized and screened for HⅣ integrase inhibition activity.The chemical structures of these compounds were confirmed by means of1H NMR 13C NMR,and ESI-MS.Preliminary bioassays indicated that calix[4]arene derivatives proved to be more active than p-tertbutylcalix[4]arene derivatives.In particular,compound 4g presented the most potent integrase strand transfer inhibitory activity with an IC50value of 6.1 mmol/L.展开更多
The title complex（C66H76O8·CH3CN） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 22.384（13）, b = 13.413（7）,...The title complex（C66H76O8·CH3CN） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 22.384（13）, b = 13.413（7）, c = 21.867（12）, β = 112.257（7）°, C68H78NO8, Mr = 1037.31, Dc = 1.133 g/cm3, V = 6076（6） 3, Z = 4, F（000） = 2224, μ（MoKa） = 0.073 mm-1, T = 296（2） K, 10276 independent reflections with 5469 observed ones（I 〉 2σ（I））, R = 0.0797 and wR = 0.2316 with GOF = 1.027（R = 0.1442 and wR = 0.2689 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O–H···O hydrogen bonds. The inhibition of the strand transfer process of HIV-1 integrase of the title compound was also evaluated. Preliminary bioassays indicated that it has a low inhibition ratio（24.85%） at the concentration of 50 μM.展开更多
A regio- and stereo-selective reduction of diketo-n-butylphosphonates by baker's yeast was reported. The chemical yield and ee value of these reactions are highly dependent on the structure of substrates. The re...A regio- and stereo-selective reduction of diketo-n-butylphosphonates by baker's yeast was reported. The chemical yield and ee value of these reactions are highly dependent on the structure of substrates. The resulting optical active hydroxy^alkanephosphonates can be used as chirons for the synthesis of polyfunctional organophosphorus compounds. As useful building block, a series of α,β-unsaturated ketones bearing chiral hydroxy group in addition to trifluoromethyl moiety was prepared via the Horner-Wadsworth-Emmons (HWE) reaction of the biotransformation products.展开更多
基金Supported by the National Natural Science Foundation of China（Nos.31100523,31171267,21173014） and the Beijing Outstanding Personnel Training Foundation,China（No.2012D005015000006）.
文摘Integrase（IN） plays an essential role in the process of HIV-1 replication.IN inhibitors of diketo acid derivatives（DKAs） were analysed by the Comparative Molecular Field Analysis（CoMFA） and Comparative Molecular Similarity Induces Analysis（CoMSIA） methods.A set of 42 compounds were randomly selected as the training set（35） and test set（7）.Firstly,a good pharmacophore（goodness of hit=0.787） was obtained and used to align ligands.Then,predictive models were constructed with the CoMFA and CoMSIA methods based on the pharmacophore alignment.As a result,the CoMS1A method yielded the best model with an r2 of 0.955 and a q2 of 0.665,which can predict the activities of the tested DKAs very well（r2=0.559）.Finally,DKAs were docked into IN,and the predicit modes were superimposed on the contour maps obtained from the best CoMSIA model.The superimposed maps gave a visualized and meaningful insight into the inhibitory behaviors,providing significantly useful information for the rational drug design of anti-IN agents.
基金Supported by the National Natural Science Foundation of China(No. 20402001)Special Foundation for Beijing Municipal In-telligent(No. 20041D0501520)Beijing Natural Science Foundation(No. 2062003).
文摘Aryl diketo acid derivatives are one of the most promising HIV-1 integrase（IN） inhibitors. With a view to substitute the critical diketo acid pharmacophore with the diketo benzimidazole unit, the coupling reaction of compound 4 with o-phenylenediamine was carried out. However, the reaction product, compound 5, was confirmed to be 3-{ [ 3- （phenylsulfonamido） benzoyl] methylidene t -3,4-dihydroquinoxaline-2 （1H） -one rather than the 2-benzimidazole derivative by using X-ray diffraction. Owing to its low solubility in water, the evaluation of the anti-HIV IN activity of the synthesized compound 5 could not be carried out. Consequently, the ion-binding properties of compound 5 in the absence of HIV-1 IN were investigated with UV-Vis spectroscopy in organic solvents. The results show that such a compound can selectively recognize Cu^2＋.
基金supported by the Natural Science Foundation of Zhejiang Province (Y. 4090578)
文摘As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HIV-1 IN. In the present work, two three-dimensional QSAR techniques （CoMFA and CoMSIA） were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search （AOS） and all-placement search （APS） were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the HIV-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent HIV-1 integrase inhibitors.
基金Supported by the Project of the Beijing Municipal Commission of Education,China(No.KM201410005030)the Importation and Development of High-caliber Talents Project of Beijing Municipal Institutions,Chinathe National Natural Science Foundation of China(No.31100523).
文摘The study dealed with quantitative structure-activity relationship(QSAR)to explore the important features of diketo acid(DKA)derivatives for exerting potent HIV-1 integrase inhibitors activity.A three-step screening method was proposed to choose descriptors.Then,additional descriptors were used in the CoMFA and CoMSIA.Lastly,a modified CoMSIA m7 model,constructed by adding Csp^2_03_F descriptor,showed better predictive ability.Validation parameters(Q^2 and R^2)for the models were 0.722 and 0.925,respectively.In addition,external validation for the models using a test group revealed R^2pred=0.892.Contour maps analysis defined favored and disfavored regions of the compounds,and two new compounds with the descriptor structure were designed with better activities than Raltegravir(RAL),well drug-likeness and low toxicity.The research provides a base for further DKA development.
基金supported by the National Natural Science Foundation of China(No.21102003)National Students'Innovation and Entrepreneurship Training Program(No.201210361094)Scientific Research Foundation for the Introduction of Talent and Young Teachers Scientific Research Foundation of Anhui University of Science&Technology(11214,2012QNY27)
文摘The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 19.434（5） A, β = 104.411（4）°, Mr = 804.85, Dc = 1.288 g/cm3, V = 4149.2（17） A3, Z = 4, F（000） = 1696, #（MoKa） = 0.089 mm-1T = 296（2） K, 7279 independent reflections with 3172 observed ones （I 〉 2δ（/））, R = 0.0520 and wR = 0.1203 with GOF = 0.928 （R = 0.1464 and wR = 0.1657 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O-H…O hydrogen bonds. Preliminary bioassays indicated that the title compound has a potent inhibitory activity against the strand transfer process of HIV-1 integrase.
基金Project supported by the National Natural Science Foundation of China （No. 20402001）, Beijing Novel Project （No. 2005B10） and Beijing Natural Science Foundation （No. 2062003）.Acknowledgements We would like to thank Prof. He, L. N. and Miss Du, Y. in College of Chemistry, Nankai University for their help in measuring NMR for a part of the compounds.
文摘Diketo acid derivatives are potent and selective HIV-1 integrase inhibitors. To investigate the detailed synthesis of those derivatives, a series of p/m-[p-（un）substituted phenylsulfonamido]phenyl β-diketo acid derivatives have been designed and synthesized. The quinoxalone derivatives as the potential bioisosteres of the biologically labile β-diketoacid pharmacophores have also been synthesized from reactions of the corresponding diketo acids with o-phenylenediamine. The structures of all diketo acid （ester） and quinoxalone derivatives were confirmed by 1^H NMR, 13^C NMR, IR, HRMS and/or MS （ESI）. X-ray crystallographic analysis of 11b demonstrates a similar arrangement of the side chain of quinoxalone derivatives with the parent diketoacids due to the intramolecular hydrogen bond （O…H-N） and the sp^2 hybridization configuration of the two nitrogen atoms of the quinoxalone ring.
基金the National Natural Science Foundation of China (Nos.21102003, 21102084, 81202438)Scientific Research Foundation for the Introduction of Talent and Young Teachers Scientific Research Foundation of Anhui University of Science & Technology (Nos. 11214, 2012QNY27) for the financial supports
文摘A series of novel calix[4]arene derivatives incorporating two triazolyl 1 3-diketo subunits in alternate positions at the lower rim were synthesized and screened for HⅣ integrase inhibition activity.The chemical structures of these compounds were confirmed by means of1H NMR 13C NMR,and ESI-MS.Preliminary bioassays indicated that calix[4]arene derivatives proved to be more active than p-tertbutylcalix[4]arene derivatives.In particular,compound 4g presented the most potent integrase strand transfer inhibitory activity with an IC50value of 6.1 mmol/L.
基金supported by the National Natural Science Foundation of China(No.21102003)National Students'Innovation and Entrepreneurship Training Program(No.201210361094)+1 种基金Scientific Research Foundation for the Introduction of TalentYoung Teachers Scientific Research Foundation of Anhui University of Science&Technology(11214,2012QNY27)
文摘The title complex（C66H76O8·CH3CN） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 22.384（13）, b = 13.413（7）, c = 21.867（12）, β = 112.257（7）°, C68H78NO8, Mr = 1037.31, Dc = 1.133 g/cm3, V = 6076（6） 3, Z = 4, F（000） = 2224, μ（MoKa） = 0.073 mm-1, T = 296（2） K, 10276 independent reflections with 5469 observed ones（I 〉 2σ（I））, R = 0.0797 and wR = 0.2316 with GOF = 1.027（R = 0.1442 and wR = 0.2689 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O–H···O hydrogen bonds. The inhibition of the strand transfer process of HIV-1 integrase of the title compound was also evaluated. Preliminary bioassays indicated that it has a low inhibition ratio（24.85%） at the concentration of 50 μM.
文摘A regio- and stereo-selective reduction of diketo-n-butylphosphonates by baker's yeast was reported. The chemical yield and ee value of these reactions are highly dependent on the structure of substrates. The resulting optical active hydroxy^alkanephosphonates can be used as chirons for the synthesis of polyfunctional organophosphorus compounds. As useful building block, a series of α,β-unsaturated ketones bearing chiral hydroxy group in addition to trifluoromethyl moiety was prepared via the Horner-Wadsworth-Emmons (HWE) reaction of the biotransformation products.
