Design, Synthesis and Cu^2＋ Recognition of β-Diketoacid and Quinoxalone Derivatives Bearing Caffeoyl or Galloyl Moieties Linked by Arylamide as Potential HIV Integrase Inhibitors

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.

A Simple and Highly Efficient Preparation of Structurally Diverse Aryl β-diketoacids as HIV-1 Integrase Inhibitors

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.

Quinoline Ring Derivatives as Potent Integrase Inhibitors Using Ligand-based Modeling Studies

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.

Synthesis and anti-integrase evaluation of novel calix[4]arene derivatives containing the triazolyl 1,3-diketo moiety

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.

Design and Synthesis of p/m-[p-（un）Substituted Phenylsulfonamido]phenyl β-Diketo Acids and Quinoxalone Derivatives

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.

The urgent need for more potent antiretroviral therapy in low-income countries to achieve UNAIDS 90-90-90 and complete eradication of AIDS by 2030

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.