Synthesis,characterization and self-assembly of novel fluorescent alkoxy-substituted 1, 4-diarylated 1, 2, 3-triazoles organogelators

Novel organogelators based on fluorescent alkoxy-substituted 1,4-diarylated 1, 2, 3-triazoles are reported. The findings monitored in the current study promoted the development of inventive compacted supramolecular architectures generated by self-assembly of the prepared triazole-based organogelators. The synthesis, characterization and gelation properties of the current novel alkoxy-substituted 1,4-diarylated 1, 2, 3-triazole arms were described. The synthesis procedures were accomplished by using Cu-catalyzed azide-alkyne cycloaddition (CuAAC) of alkoxy-substituted aryl azide with aryl bearing terminal alkyne subtituents and alkoxy chains of different lengths. The alkoxy-substituted of 1, 4-diarylated 1, 2, 3-triazole derivatives bearing different alkoxy chains were characterized by FTIR, ¹H/¹³C NMR, and elemental analysis. The 1, 4-diarylated 1, 2, 3-triazoles with longer alkoxy terminal groups demonstrated improved gelation properties compared to those with shorter alkoxy terminals. The morphologies of the self-assembled alkoxy-substituted 1, 4-diarylated 1, 2, 3-triazoles were investigated using scanning electron microscopy (SEM), which demonstrated arrangements of highly ordered nanofibers, forced by π-stacks and van der Waals interactions. The antibacterial activity and cytotoxicity of the newly synthesized triazoles was investigated to verify the potential use of the present triazole gelators for a variety of applications, such as drug delivery.     

Possible allosteric interactions of monoindazole-substituted P2 cyclic urea analogues with wild-type and mutant HIV-1 protease

Our ongoing efforts to understand the difference in the binding pattern of HIV-1 protease inhibitor (HIVPI) with the wild-type and mutant HIV-1 protease (HIVPR) and to provide mechanistic insight are continued further. We report here the results of a recent quantitative structure-activity relationship (QSAR) study on monoindazole-substituted P2 analogues of cyclic urea HIVPIs. The QSAR models revealed an inverted parabolic relationship between biological activity and calculated molar refractivity (CMR). That is, biological activity first decreases with increase in CMR and at a certain minimum point (inversion point) it suddenly changes and increases with further increase in CMR. CMR is a measure of volume-dependent-polarizability and is an indication of the polar interactions between ligand and receptor. The results seem to be best rationalized by larger molecules inducing a change in a receptor unit that allows for a new mode of interaction. Similar QSAR models were also observed for the biological activity of these molecules tested against a panel of mutant viruses including mutant strains with single amino acid substitution (I84V), double amino acid substitutions (I84V/V82F), and multiple amino acid changes corresponding to mutations observed in clinical isolates of patients treated with Ritonavir((R)). Interestingly the inversion points for these mutant strains were found larger than for wild-type. The subtle but significant difference in the inversion point indicates change in the shape and size of the binding pocket. Earlier QSAR studies have shown that the correlation of biological activity with an inverted parabola is an indicative of the 'allosteric interaction' of the ligands with the receptor. This report presents a detail analysis of these observations.     

Synthesis of novel HIV-1 protease inhibitors via diastereoselective Henry reaction with nitrocyclopropane

Novel reaction and work-up conditions were developed for the unprecedented Henry reaction using nitrocyclopropane in the key step towards the synthesis of HIV-1 protease inhibitors. This procedure may find application in the preparation of diverse compounds of potential biological interest.     

金属离子对HIV-1整合酶与硫氮硫扎平抑制剂作用模式影响的分子模拟研究

HIV-1整合酶（IN）通过依赖金属离子的两步反应将病毒DNA整合入宿主细胞过程中。结合于HIV-1上的金属离子个数的变化直接影响整合酶与抑制剂之间的结合。本工作用同源模建方法搭建了每条单链核心区具有两个Mg2+ 的（2Mg-IN-Core）和具有一个Mg2+ 的HIV-1 IN二聚体核心区模型（1Mg-IN-Core）。分子对接分别得到它们与硫氮硫扎平类化合物能量较低的复合物结构,把对接结果进行了比较。研究发现：当整合酶中结合的Mg2+个数改变时,它与抑制剂的结合模式也会发生很大的变化;抑制剂能够特异的且稳定的与2Mg-IN-Core模型的活性位点结合;同时与ASP64和GLU152螯合的那个Mg2+离子对于硫氮硫扎平抑制剂与整合酶上的结合有很大的影响。2Mg-IN-Core模型与抑制剂的复合物平均结构进行了2000 ps的 分子动力学模拟,分析发现同时与ASP64及ASP116螯合的Mg2+与IN蛋白形成了四个稳定的螯合键;同时与ASP64及GLU152螯合的Mg2+可与IN结合、也可与抑制剂形成稳定的配位键,这个Mg2+对IN与硫氮硫扎平抑制剂之间的结合有较大影响。     

Synthesis and crystal structures of polynuclear complexes of Cu with 1-methyl-1,3-imidazoline-2-thione

Reactions of equimolar solutions of copper(I) halides with 1-methyl-1,3-imidazoline-2-thione (SC₄H₆N₂) in acetonitrile have yielded a trinuclear complex, {Cu₃(η¹-Br)₃(μ-SC₄H₆N₂)₃} · CH₃CN 1, and 1D polymer, {Cu₂(μ-I)₂(μ-SC₄H₆N₂)₂}_n2. The thio-ligands/halogens adopt μ-S, η¹-X or μ-X modes. There is weak interaction between trinuclear units {Cu···Br, 3.025 Å} and Cu···Cu contacts lie in the range, 2.974(2)–3.650(2) Å. Polymer 2 has alternating Cu₂I₂ and Cu₂S₂ cores involving sulfur/iodine bridging in a twisted ribbon type arrangement with short Cu···Cu distances {2.6912(9) and 2.785(9) Å}, respectively. The polynuclear complexes in dimethyl sulfoxide exhibit intense fluorescent bands {λ_em = 319 (1) and 322 (2)}.     

Study on the drug resistance and the binding mode of HIV-1 integrase with LCA inhibitor

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. The binding mode of the wild type IN core domain and its G140S mutant with L-Chicoric acid (LCA) inhibitor were investigated by using multiple conformation molecular docking and molecular dynamics (MD) simulation. Based on the binding modes, the drug resistance mechanism was explored for the G140S mutant of IN with LCA. The results indicate that the binding site of the G140S mutant of IN core domain with LCA is different from that of the core domain of the wild type IN, which leads to the partial loss of inhibition potency of LCA. The flexibility of the IN functional loop region and the interactions between Mg2 ion and the three key residues (i.e., D64, D116, E152) stimulate the biological operation of IN. The drug resistance also lies in several other important effects, such as the repulsion between LCA and E152 in the G140S mutant core domain, the weakening of K159 binding with LCA and Y143 pointing to the pocket of the G140S mutant. All of the above simulation results agree well with experimental data, which provide us with some helpful information for designing the drug of anti-HIV based on the structure of IN.     

Design and synthesis of á, á-trehalose derivatives bearing guanidino groups as inhibitors for the Tat Protein-TAR RNA interaction of HIV-1

Replication of human immunodeficiency virus type 1 (HIV-1) requires specific interactions of Tat protein with the transactivation responsive region (TAR) RNA. Disruption of Tat-TAR RNA interaction could inhibit HIV-1 replication. Here four target compounds were designed and synthesized to bind to TAR RNA for blocking the interaction of Tat-TAR RNA. The core molecule 6,6'-diamino-6,6' -dideoxy-α,α-trehalose was obtained from selective bromination of α,α-trehalose at C-6,6', fo…     

酪氨酸与1-亚硝基-2-萘酚反应的研究

本文用荧光、分子吸收光谱和电化学等方法研究了在含 Na NO2 的 HNO3溶液中酪氨酸与 1 -亚硝基 - 2 -萘酚的反应 ,该反应最后生成具有荧光性质的酚噻嗪类化合物。于 - 0 .5 3V( vs. SCE)处被还原的反应中间物酚噻嗪类化合物的氧化物可被光还原为酚噻嗪类化合物 ,其分解过程的反应为二级反应 ;反应速度常数为 5× 1 0 - 4L· mol- 1· min- 1。酚噻嗪类化合物的生成过程为一级反应 ,反应速度常数为 0 .0 2 1min     

Synthesis, structure and spectral study of two types of novel fluorescent BF2 complexes with heterocyclic 1,3-enaminoketone ligands

Two types of novel BF₂ complexes are readily obtained by the reaction of BF₃OEt with 3-(2-oxo-2-arylethylidene)-3,4-dihydro-1H-quinoxalin-2-ones or 3-(2-oxo-2-arylethylidene)-3,4-dihydrobenzo[1,4]oxazin-2-ones, respectively in refluxing acetic acid/toluene solvent mixture. The complexes are confirmed by elemental analysis, FT-IR, ¹H, ¹³C, ¹¹B, ¹⁹F NMR and one of them is executed its X-ray crystallographic study. The outstanding photophysical properties of these complexes are determined by UV–vis absorption and fluorescence emission spectroscopy.     

Synthesis,structure and fluorescent properties of CdII,ZnII and NiII complexes with 2-amino-6-methylbenzothiazole and 5-nitroisophthalate as ligands

Three new coordination polymers, [M(Ambt)₂(Nip)] _n (M = Cd for 1 and Zn for 2) and [Ni_0.5(Nip)(H₂O)₂] (HAmbt) (3) (H₂Nip = 5-nitroisophthalic acid, Ambt = 2-amino-6-methylbenzothiazole), have been synthesized by hydrothermal methods and are further characterized by X-ray diffraction, IR spectra, elemental analysis, TG-DTA and fluorescence spectra. The structural analyses suggest that 1 and 2 are 1-D chains bridged by Nip anions, in which Ambt is a monodentate ligand and the carboxylate groups of Nip are monodentate and chelating bidentate. Complex 3 consists of two individual fragments, six-coordinate mononuclear Ni^II and HAmbt cation, in which HAmbts are encapsulated into the concave of the 2-D layer formed by mononuclear units through classic N?H·· · O hydrogen bonds. Abundant hydrogen bond interactions drive the formation of packing structure of the complexes. The three solid complexes display strong emission peaks from intraligand charge transfer similar to free Ambt at room temperature.     

用分子对接方法研究HIV-1整合酶与病毒DNA的结合模式

用分子对接方法研究了HIV-1整合酶(Integrase, IN)二聚体与3’ 端加工(3’ Processing, 3’-P)前的8 bp及27 bp病毒DNA的相互作用, 并获得IN与27 bp病毒DNA的特异性结合模式. 模拟结果表明, IN有特异性DNA结合区和非特异性DNA结合区; IN二聚体B链的K14, R20, K156, K159, K160, K186, K188, R199和A链的K219, W243, K244, R262, R263是IN结合病毒DNA的关键残基; 并从结构上解释了能使IN发挥活性的病毒DNA的最小长度是15 bp. 通过分析结合能发现, IN与DNA稳定结合的主要因素是非极性相互作用, 而关键残基与病毒DNA相互识别主要依赖于极性相互作用. 模拟结果与实验数据较吻合.     

Synthesis and Antiviral Activity of 1-{[2-(Phenoxy)ethoxy]methyl}uracil Derivatives

The synthesis of novel 1-{[2-(phenoxy)ethoxy]methyl}uracil derivatives with different substituents in positions and 6 of the pyrimidine ring has been carried out. It has been shown that the alkylation of trimethylsilyl derivatives of uracil with 2-(4-chlorophenoxy)- and 2-(4-methylphenoxy)ethoxymethyl chloride under Hilbert-Johnson reaction conditions gives N₍₁₎-substitution products. It was found that the 1-{ [2-(phenoxy)ethoxy]methyl}uracil derivatives show viral inhibition properties relative to human immunodeficiency type 1 virus in vitro. The most active compounds are 5-bromo-6-methyluracil derivatives which suppress viral reproduction by 50% at 7.2 and 7.8 micromolar concentrations.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 726–731, May, 2005.     

1-乙酰基-3-(2-羟基-4,6-二甲氧基苯基)-5-芳基-2-吡唑啉的合成及Cu2+荧光探针行为

设计合成了6个1-乙酰基-3-(2-羟基-4,6二甲氧基苯基)-5-芳基-2-吡唑啉化合物4a～4f.测试了它们的紫外光谱和荧光光谱,研究了其对铜离子的选择性识别作用.结果表明,化合物4f作为铜离子荧光探针,受常见离子干扰较小,对于铜离子有着较高的选择性和较低的检出限.     

1-乙酰基-3-(2-羟基-4,6-二甲氧基苯基)-5-苯基-2-吡唑啉的合成及锌离子探针的研究

设计合成了1-乙酰基-3-(2-羟基-4,6-二甲氧基苯基)-5-苯基-2-吡唑啉(4), 测试了其紫外光谱和荧光光谱, 研究了其对锌离子的选择性识别作用. 结果表明, 化合物4作为锌离子荧光探针, 受常见离子的干扰较小, 对于锌离子有着较高的选择性和较低的检出限.     

Synthesis and In Vitro Study of Antiviral Activity of Glycyrrhizin Nicotinate Derivatives against HIV-1 Pseudoviruses and SARS-CoV-2 Viruses

When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC₅₀2–8 μM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC₅₀ range 3.9–27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.     

Radical Cyclization of 1,n-Enynes and 1,n-Dienes for the Synthesis of 2-Pyrrolidone

2-Pyrrolidones have aroused enormous interest as a useful structural moiety in drug discovery; however, not only does their syntheses suffer from low selectivity and yield, but also it requires high catalyst loadings. The radical cyclization of 1,n-enynes and 1,n-dienes has demonstrated to be an attractive method for the synthesis of 2-pyrrolidones due to its mild reaction conditions, fewer steps, higher atom economy, excellent functional group compatibility, and high regioselectivity. Furthermore, radical receptors with unsaturated bonds (i. e. 1,n-enynes and 1,n-dienes) play a crucial role in realizing radical cyclization because of the ability to selectively introduce one or more radical sources. In this review, we discuss representative examples of methods involving the radical cyclization of 1,n-enynes and 1,n-dienes published in the last five years and discuss each prominent reaction design and mechanism, providing favorable tools for the synthesis of valuable 2-pyrrolidone for a variety of applications.     

吡咯并[2,1,5-cd]中氮茚酰腙衍生物的合成及Cu2+荧光探针行为

设计合成了吡咯并[2,1,5-cd]中氮茚酰腙衍生物6. 测试了其紫外光谱和荧光光谱, 研究了其对铜离子的选择性识别作用. 结果表明, 化合物6作为铜离子荧光探针, 受常见离子干扰较小, 对于铜离子有着较高的选择性和较低的检出限.