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
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
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
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
建立了利用高效液相色谱对葡萄糖发酵产2-酮基-L-古龙酸体系中的4种代谢产物D-葡萄糖酸、2-酮基-D-葡萄糖酸、2,5-二酮基-D-葡萄糖酸和2-酮基-L-古龙酸的定量测定方法,分析条件为:300mm×7.8 mm AminexHPX-87H柱,柱温30℃,流动相为5...建立了利用高效液相色谱对葡萄糖发酵产2-酮基-L-古龙酸体系中的4种代谢产物D-葡萄糖酸、2-酮基-D-葡萄糖酸、2,5-二酮基-D-葡萄糖酸和2-酮基-L-古龙酸的定量测定方法,分析条件为:300mm×7.8 mm AminexHPX-87H柱,柱温30℃,流动相为50mmol/L硫酸,流速0.2mL/min,RID-10A示差检测器,以丙二酸为内标物.结果表明,4种物质分离较好.该方法对2-酮基-D-葡萄糖酸、2,5-二酮基-D-葡萄糖酸和2-酮基-L-古龙酸3种代谢物的检测平均误差分别为1.53%,0.89%和1.84%.展开更多
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 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 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.
文摘建立了利用高效液相色谱对葡萄糖发酵产2-酮基-L-古龙酸体系中的4种代谢产物D-葡萄糖酸、2-酮基-D-葡萄糖酸、2,5-二酮基-D-葡萄糖酸和2-酮基-L-古龙酸的定量测定方法,分析条件为:300mm×7.8 mm AminexHPX-87H柱,柱温30℃,流动相为50mmol/L硫酸,流速0.2mL/min,RID-10A示差检测器,以丙二酸为内标物.结果表明,4种物质分离较好.该方法对2-酮基-D-葡萄糖酸、2,5-二酮基-D-葡萄糖酸和2-酮基-L-古龙酸3种代谢物的检测平均误差分别为1.53%,0.89%和1.84%.
