An efficient procedure for the synthesis of caffeoyl- and galloyl-containing β-diketoacid derivatives linked by arylamide was reported by, in the key step, dissolving the corresponding phenyl methyl ketone in THF/DME...An efficient procedure for the synthesis of caffeoyl- and galloyl-containing β-diketoacid derivatives linked by arylamide was reported by, in the key step, dissolving the corresponding phenyl methyl ketone in THF/DME in the presence of NaOMe as base and dimethyl oxalate as oxalylation reagent, and then separating the sodium ketoenolate ester. The resulting β-diketoacids underwent further condensation reaction with o-phenylenediamine to generate quinoxalone derivatives in good yield, rather than 2-benzimidazol. The preliminary ion binding properties of quinoxalone derivatives were also investigated. UV-Vis spectra showed that these compounds could selectively recognize Cu^2 ＋ ion in ethanol and form a 1 ： 2 complex.展开更多
In order to provide a facile and practical access to structurally diverse aryl -diketoacids, An improved and highly efficient oxalylation method was developed which employed commercially available and cheap reagents. ...In order to provide a facile and practical access to structurally diverse aryl -diketoacids, An improved and highly efficient oxalylation method was developed which employed commercially available and cheap reagents. The oxalylation of aryl methyl ketones, the key step to construct the pharmacophore of aryl -diketoacids, was con-siderably facilitated by a new combination of dimethyl oxalate as an oxalic source and sodium tert-butoxide as a base. A wide variety of aryl -diketoacids bearing different functional groups can be prepared rapidly in high yields at room temperature with this method, which has significant advantages over the previously reported procedures in a wider application range, much less amount of reagents, pretty higher yields and quite shorter reaction time. The bis-aryldiketoacids 3k and 3l, readily prepared by this method, displayed interesting and promising inhibitory ac-tivities against HIV-1 integrase and HIV-1 replication in cells.展开更多
Integrase has become an attractive target for the design of anti-HIV inhibitor because it plays a quite important role in the process of HIV-1 virus replication. The quinoline ring derivatives, which have the similar ...Integrase has become an attractive target for the design of anti-HIV inhibitor because it plays a quite important role in the process of HIV-1 virus replication. The quinoline ring derivatives, which have the similar pharmacophore toβ-diketoacids, are the kind of integrase inhibitor with highly antiviral activity. A series of quinoline ring derivatives were analyzed by the comparative molecular field analysis(Co MFA), comparative molecular similarity induces analysis(Co MSIA) and Topomer Co MFA methods. Firstly, we chose 77 compounds from former papers as a dataset,followed by dividing it into the training set and test set randomly. Then, we constructed predictive models of Co MFA, Co MSIA and Topomer Co MFA, respectively. The Co MFA yielded the best cross-validated model with a q2=0.758, non-cross-validated r2=0.988.The Co MSIA model yielded a q2=0.701 and r2=0.986 while the Topomer Co MFA model has q2=0.661 and r2=0.966. Through verification, these results suggested a strong predictive ability to the design of novel highly active HIV-1 integrase inhibitors for therapy.展开更多
Integrase strand transfer inhibitors(INSTIs)have emerged as the first‐line choice for treating human immunodeficiency virus(HIV)infection due to their superior efficacy and safety.However,the impact of INSTIs on the ...Integrase strand transfer inhibitors(INSTIs)have emerged as the first‐line choice for treating human immunodeficiency virus(HIV)infection due to their superior efficacy and safety.However,the impact of INSTIs on the development of neuropsychiatric conditions in people living with HIV(PLWH)is not fully understood due to limited data.In this study,we conducted a cross‐sectional examination of PLWH receiving antiretroviral therapy,with a specific focus on HIV‐positive men who have sex with men(MSM)on INSTI‐based regimens(n=61)and efavirenz(EFV)‐based regimens(n=28).Participants underwent comprehensive neuropsychiatric evaluations and multimodal magnetic resonance imaging(MRI)scans,including T1‐weighted images and resting‐state functional MRI.Compared to the EFV group,the INSTI group exhibited primarily reduced gray matter volume(GMV)in the right superior parietal gyrus,higher regional homogeneity(ReHo)in the left postcentral gyrus,lower ReHo in the right orbital part of the inferior frontal gyrus,and increased voxel‐wise functional connectivity for the seed region in the left inferior temporal gyrus with clusters in the right cuneus.Furthermore,the analysis revealed a main effect of antiretroviral drugs on GMV changes,but no main effect of neuropsychiatric disorders or their interaction.The repeated analysis of participants who did not switch regimens confirmed the GMV changes in the INSTI group,validating the initial findings.Our study demonstrated gray matter atrophy and functional brain changes in PLWH on INSTI‐based regimens compared to those on EFV‐based regimens.These neuroimaging results provide valuable insights into the characteristics of brain network modifications in PLWH receiving INSTI‐based regimens。展开更多
In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed b...In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed by electrospray ionization mass spectrometry （ESI-MS） and circular dichroism （CD）.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
Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this numbe...Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this number will be approximately 36.4 million people with over 98%in low-income countries(LICs).Main body:Pretreatment drug resistance(PDR)largely driven by frequently use of non-nucleoside reverse transcriptase inhibitors(NNRTIs),efavirenz and nevirapine,has been increasing with roll-out of combined antiretroviral therapy(cART)with 29%annual increase in some LICs countries.PDR has exceeded 10%in most LICs which warrants change of first line regimen to more robust classes under WHO recommendations.If no change in regimens is enforced in LICs,it’s estimated that over 16%of total deaths,9%of new infections,and 8%of total cART costs will be contributed by HIV drug resistance by 2030.Less than optimal adherence,and adverse side effects associated with currently available drug regimens,all pose a great threat to achievement of 90%viral suppression and elimination of AIDS as a public health threat by 2030.This calls for urgent introduction of policies that advocate for voluntary and compulsory drug licensing of new more potent drugs which should also emphasize universal access of these drugs to all individuals worldwide.Conclusions:The achievement of United Nations Programme on HIV and AIDS 2020 and 2030 targets in LICs depends on access to active cART with higher genetic barrier to drug resistance,better safety,and tolerability profiles.It’s also imperative to strengthen quality service delivery in terms of retention of patients to treatment,support for adherence to cART,patient follow up and adequate drug stocks to help achieve a free AIDS generation.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
基金Project supported by the National Natural Science Foundation of China （No. 20402001）, the Special Foundation for Beijing Municipal （No. 2004D0501520 and Beijing Novel Project （No. 2005B 10）.
文摘An efficient procedure for the synthesis of caffeoyl- and galloyl-containing β-diketoacid derivatives linked by arylamide was reported by, in the key step, dissolving the corresponding phenyl methyl ketone in THF/DME in the presence of NaOMe as base and dimethyl oxalate as oxalylation reagent, and then separating the sodium ketoenolate ester. The resulting β-diketoacids underwent further condensation reaction with o-phenylenediamine to generate quinoxalone derivatives in good yield, rather than 2-benzimidazol. The preliminary ion binding properties of quinoxalone derivatives were also investigated. UV-Vis spectra showed that these compounds could selectively recognize Cu^2 ＋ ion in ethanol and form a 1 ： 2 complex.
基金Shanghai Municipal Committee of Science and Technology (Nos.02QB14056 and 03DZ19219)the Chinese Academy of Sciences (KSCX1-SW-11)the Ministry of Personnel of China.
文摘In order to provide a facile and practical access to structurally diverse aryl -diketoacids, An improved and highly efficient oxalylation method was developed which employed commercially available and cheap reagents. The oxalylation of aryl methyl ketones, the key step to construct the pharmacophore of aryl -diketoacids, was con-siderably facilitated by a new combination of dimethyl oxalate as an oxalic source and sodium tert-butoxide as a base. A wide variety of aryl -diketoacids bearing different functional groups can be prepared rapidly in high yields at room temperature with this method, which has significant advantages over the previously reported procedures in a wider application range, much less amount of reagents, pretty higher yields and quite shorter reaction time. The bis-aryldiketoacids 3k and 3l, readily prepared by this method, displayed interesting and promising inhibitory ac-tivities against HIV-1 integrase and HIV-1 replication in cells.
文摘Integrase has become an attractive target for the design of anti-HIV inhibitor because it plays a quite important role in the process of HIV-1 virus replication. The quinoline ring derivatives, which have the similar pharmacophore toβ-diketoacids, are the kind of integrase inhibitor with highly antiviral activity. A series of quinoline ring derivatives were analyzed by the comparative molecular field analysis(Co MFA), comparative molecular similarity induces analysis(Co MSIA) and Topomer Co MFA methods. Firstly, we chose 77 compounds from former papers as a dataset,followed by dividing it into the training set and test set randomly. Then, we constructed predictive models of Co MFA, Co MSIA and Topomer Co MFA, respectively. The Co MFA yielded the best cross-validated model with a q2=0.758, non-cross-validated r2=0.988.The Co MSIA model yielded a q2=0.701 and r2=0.986 while the Topomer Co MFA model has q2=0.661 and r2=0.966. Through verification, these results suggested a strong predictive ability to the design of novel highly active HIV-1 integrase inhibitors for therapy.
基金supported by the National Natural Science Foundation of China(82072271,82241072,82072294)the National Key Research and Development Program of China(2021YFC2501402,2021YFC0122601)+8 种基金the Beijing Natural Science Foundation(7222095,7222091)the Peak Talent Program of Beijing Hospital Authority(DFL20191701)the Capital’s Funds for Health Improvement and Research(2022-1-1151)the Research and Translational Application of Clinical Characteristic Diagnostic and Treatment Techniques in Capital City(Z221100007422055)the Beijing Research Center for Respiratory Infectious Diseases(BJRID2024-001)the Beijing Hospitals Authority Innovation Studio of Young Staff Funding Support(2021037)the High-level Public Health Technical Personnel Construction Project(2022-1-007)the High-level Public Health Specialized Talents Project of Beijing Municipal Health commission(2022-02-20)the Beijing Key Laboratory for HIV/AIDS Research(BZ0089).
文摘Integrase strand transfer inhibitors(INSTIs)have emerged as the first‐line choice for treating human immunodeficiency virus(HIV)infection due to their superior efficacy and safety.However,the impact of INSTIs on the development of neuropsychiatric conditions in people living with HIV(PLWH)is not fully understood due to limited data.In this study,we conducted a cross‐sectional examination of PLWH receiving antiretroviral therapy,with a specific focus on HIV‐positive men who have sex with men(MSM)on INSTI‐based regimens(n=61)and efavirenz(EFV)‐based regimens(n=28).Participants underwent comprehensive neuropsychiatric evaluations and multimodal magnetic resonance imaging(MRI)scans,including T1‐weighted images and resting‐state functional MRI.Compared to the EFV group,the INSTI group exhibited primarily reduced gray matter volume(GMV)in the right superior parietal gyrus,higher regional homogeneity(ReHo)in the left postcentral gyrus,lower ReHo in the right orbital part of the inferior frontal gyrus,and increased voxel‐wise functional connectivity for the seed region in the left inferior temporal gyrus with clusters in the right cuneus.Furthermore,the analysis revealed a main effect of antiretroviral drugs on GMV changes,but no main effect of neuropsychiatric disorders or their interaction.The repeated analysis of participants who did not switch regimens confirmed the GMV changes in the INSTI group,validating the initial findings.Our study demonstrated gray matter atrophy and functional brain changes in PLWH on INSTI‐based regimens compared to those on EFV‐based regimens.These neuroimaging results provide valuable insights into the characteristics of brain network modifications in PLWH receiving INSTI‐based regimens。
基金the National Natural Science Foundation of China(No.20472009)the Research Fund for the Doctoral Program of Higher Education.
文摘In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed by electrospray ionization mass spectrometry （ESI-MS） and circular dichroism （CD）.
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.
文摘Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this number will be approximately 36.4 million people with over 98%in low-income countries(LICs).Main body:Pretreatment drug resistance(PDR)largely driven by frequently use of non-nucleoside reverse transcriptase inhibitors(NNRTIs),efavirenz and nevirapine,has been increasing with roll-out of combined antiretroviral therapy(cART)with 29%annual increase in some LICs countries.PDR has exceeded 10%in most LICs which warrants change of first line regimen to more robust classes under WHO recommendations.If no change in regimens is enforced in LICs,it’s estimated that over 16%of total deaths,9%of new infections,and 8%of total cART costs will be contributed by HIV drug resistance by 2030.Less than optimal adherence,and adverse side effects associated with currently available drug regimens,all pose a great threat to achievement of 90%viral suppression and elimination of AIDS as a public health threat by 2030.This calls for urgent introduction of policies that advocate for voluntary and compulsory drug licensing of new more potent drugs which should also emphasize universal access of these drugs to all individuals worldwide.Conclusions:The achievement of United Nations Programme on HIV and AIDS 2020 and 2030 targets in LICs depends on access to active cART with higher genetic barrier to drug resistance,better safety,and tolerability profiles.It’s also imperative to strengthen quality service delivery in terms of retention of patients to treatment,support for adherence to cART,patient follow up and adequate drug stocks to help achieve a free AIDS generation.
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.
