Design,Synthesis and Biological Evaluation of Novel N‐(4‐([2,2′:5′,2′′‐Terthiophen]‐5‐yl)‐2‐methylbut‐3‐yn‐2‐yl) Benzamide Derivatives

On the basis of the principle of combination of active groups, a series of novel N‐(4‐([2,2′:5′,2′′‐terthiophen]‐5‐yl)‐2‐methylbut‐3‐yn‐2‐yl) benzamide derivatives were designed, synthesized and systematically evaluated for their antiviral activity against tobacco mosaic virus (TMV). The bioassay results showed that most of these compounds displayed good anti‐TMV activity, and some of them exhibited higher antiviral activity than commercial Ningnanmycin. Especially, compound 8e with excellent anti‐TMV activity (inactivation activity, 92.3%/500 µg·mL^?1; curative activity, 85.7%/500 µg·mL^?1 and protection activity, 64.7%/500 µg·mL^?1) emerged as a potential inhibitor of plant virus TMV. Quantitative structure‐activity relationship studies proved that the van der Waals volume (V) and electronic parameter (∑(∑σ_o+σ_p) and ∑σ_m) for the substituent R¹ were very important for antiviral activities in this class of compounds.     

Ring‐opening polymerization of benzylated 1,6‐anhydro‐β‐D‐lactose and specific biological activities of sulfated (1→6)‐α‐D‐lactopyranans

A new anhydro disaccharide monomer, 1,6‐anhydro‐2,3‐di‐o‐benzyl‐4‐o‐(2′,3′,4′,6′‐tetra‐o‐benzyl‐β‐D ‐galactopyranosyl)‐β‐D ‐glucopyranose (benzylated 1,6‐anhydro lactose (LSHBE)), was synthesized from D ‐lactose to investigate the polymerizability and biological activities of the resulting branched polysaccharides. The ring‐opening polymerization of LSHBE was carried out with phosphorus pentafluoride as a catalyst under high vacuum to give a stereoregular benzylated (1 → 6)‐α‐D ‐lactopyranan. The molecular weights of poly(LSHBE)s increased with an increase in the amount of CH₂Cl₂ solvent, and polymerization temperatures were affected in both molecular weights and yields of the polymers. The copolymerization of LSHBE with benzylated 1,6‐anhydro‐β‐D ‐glucopyranose (LGTBE) gave the corresponding copolysacchrides having different proportions of lactose and glucose units in good yields. After debenzylation to recover hydroxyl groups and then sulfation, sulfated homopoly(lactose)s and copoly(lactose and glucose)s were obtained. Sulfated homopoly(lactose)s had moderate anti‐HIV (EC₅₀ = 5.9 and 1.3 μg/mL) and blood anticoagulant activities (AA = 18 and 13 unit/mg), respectively. Sulfated copoly(lactose and glucose) having 15 mol % lactose units gave high anti‐HIV and blood anticoagulant activities of 0.3 μg/mL and 54 unit/mg, respectively. These biological results suggest that the distance between branched units on the main chain plays an important role in the anti‐HIV and blood anticoagulant activities. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 913–924, 2009     

Flavonoids Isolated from Heat‐Processed Epimedium koreanum and Their Anti‐HIV‐1 Activities

Systematic phytochemical investigation on heat‐processed Epimedium koreanum led to the isolation of 13 flavonoids, including five new prenyl‐flavonol glycosides, koreanosides A–E ( 1 – 5 , resp.). Their structures were elucidated on the basis of detailed analysis of the 1D‐ and 2D‐NMR spectroscopic data and chemical reactions. Apigenin ( 11 ) exhibited moderate anti‐HIV‐1 activity with an EC₅₀ value of 12.8±3.27 μg/ml.     

Synthesis and Anti‐HIV Activity of Triazolo‐Fused,Medium‐Sized Cyclic Nucleoside Analogs Prepared by an Intramolecular Huisgen 1,3‐Dipolar Cycloaddition

Medium‐sized cyclic nucleosides containing a fused triazole ring were synthesized via intramolecular Huisgen 1,3‐dipolar cycloadditon reaction. 2′,3′‐seco‐Uridine was employed as the key intermediate for the introduction of azido and alkynyl moieties in the defined positions of the reaction precursors. The cycloaddition reactions were achieved in high yields by heating the precursor in refluxing toluene. The uracil base in these target compounds was successfully transformed to the corresponding cytosine. The synthesized compounds were evaluated in a MAGI assay for their anti‐HIV activities, and in a H9 T lymphocytes assay for their cell toxicities.     

Anti‐AIDS active polyrotaxane‐AZT conjugates with bioactive bulky stoppers and their nanoparticles

New anti‐HIV active agents, polyrotaxane‐AZT conjugates with various bioactive bulky stoppers such as 3′‐azido‐3′‐deoxythymidine (AZT) and tocopherol and their nanoparticles were synthesized and characterized. The degree of AZT substitution of the conjugates was calculated from ELEM . ANAL and ranged from 1.8 to 5.9, respectively. The in vitro antiviral activity of these conjugates was determined and used to evaluate their potential applications in anti‐AIDS drugs. The in vitro anti‐HIV activities indicate that the synthesized polyrotaxane‐AZT conjugates and their nanoparticles against HIV‐1 and HIV‐2 strains were more potent inhibitors than free AZT, with reduced cytotoxicities against uninfected MT‐4 cells. The effect of the conjugates against HIV‐1 and HIV‐2 strains increased with decreasing particle size. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Alpha‐1 antitrypsin variants in plasma from HIV‐infected patients revealed by proteomic and glycoproteomic analysis

Novel tools are necessary to explore proteins related to human immunodeficiency virus (HIV) infection. In this work, proteomic and glycoproteomic technology were employed to examine plasma samples from HIV‐positive patients. Through comparative proteome analysis of normal and HIV‐positive plasma samples, 19 differentially expressed protein spots related to 12 non‐redundant proteins were identified by ESI‐ion trap MS. Among these, the 130‐kDa isoform of α‐1‐antitrypsin was found to be decreased in HIV‐positive patients while another variant with a molecular weight of 40 kDa was increased. SWISS‐2‐D‐PAGE reference gel and protein sequence comparisons of the 40‐kDa protein showed homology with α‐1‐antitrypsin minus the N‐terminus, and its identity was further confirmed by 1‐D Western blotting and glycoproteomic analysis. In all, our results showed that proteomics and glycoproteomics are powerful tools for discovering proteins related to HIV infection. Furthermore, this 40‐kDa variant of α‐1‐antitrypsin found in the plasma of HIV‐positive individuals may prove to be a potentially useful biomarker for anti‐HIV research according to bioinformatics analysis.     

Synthesis and bioactivities of 1,3,2‐benzodiazaphosphorin‐2‐carboxamide 2‐oxides containing α‐aminophosphonate groups

In order to search for novel antitumor and antiviral agents with high activity and low toxicity, a series of 1‐ethoxycarbonylmethyl‐3‐ethyl‐1,2,3,4‐tetrahydro‐4‐oxo‐1,3,2‐benzodiazaphosphorin‐2‐carboxamide 2‐oxides containing α‐aminophosphonate groups have been designed and synthesized by a convenient one‐pot procedure in good yields. The structures of products were confirmed by ¹H NMR, ³¹P NMR, IR spectra, and elemental analyses. The bioassay results showed that some of them possess excellent anti–tobacco mosaic virus activities and exhibit higher inhibitory effects compared with that of the contrast drug 2,4‐dioxyhexahydro‐1,3,5‐triazine. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:97–101, 2001     

Anti‐inflammatory Activity of Two New Indole Alkaloids from the Stems of Nauclea officinalis

Two new indole alkaloid derivatives ( 1 , 2 ), together with six known indole alkaloids ( 3  –  8 ) were isolated from the 70% EtOH/H₂O extract of the stem of Nauclea officinalis. Their structures were determined on the basis of extensive analyses of spectroscopic data (IR, MS, 1D‐ and 2D‐NMR). All the isolates were evaluated for their anti‐inflammatory activities on lipopolysaccharide (LPS)‐induced nitric oxide (NO) production in RAW 264.7, and all the compounds showed significant inhibitory activities with the IC₅₀ values of 0.82, 6.45, 9.75, 1.34, 3.40, 2.69, 1.58, and 1.96 μm , compared to the positive drug control group aminoguanidine with an IC₅₀ value of 1.80 μm , especially compound 1 had the most significant activity.     

Synthesis of polymethacrylate derivatives having sulfated maltoheptaose side chains with anti‐HIV activities

Anti‐HIV (human immunodeficiency virus) active polymethacrylates having pendant sulfated oligosaccharides were synthesized, and the relationship between structures and biological activities of the polymethacrylates was examined. Acetylated 1‐O‐methacryloyl maltoheptaoside (MA‐AcM7) was polymerized with AIBN as an initiator to give polymethacrylates having a pendant acetylated maltoheptaose in every repeating unit, poly(MA‐AcM7)s. After hydroxyl groups were recovered by deacetylation, the polymethacrylates having maltoheptaose units, poly(MA‐M7)s, were sulfated to give polymethacrylates having sulfated maltoheptaose side‐chains, poly(MA‐SM7)s, with degrees of sulfation of 1.1 to 2.7 (maximum, 3.0). These polymethacrylates including sulfated oligosaccharides exhibited low anti‐HIV activities represented by the 50% protecting concentration (EC₅₀) in the range of 15–62 μg/mL and low blood anticoagulant activities around 10 unit/mg (standard dextran sulfate, 22.7 unit/mg). The anti‐HIV activity increased with increasing degree of sulfation to reach EC₅₀ of 15–16 μg/mL. In addition, copolymerization of MA‐AcM7 with methyl methacrylate (MMA) and subsequent sulfation gave polymethacrylates consisting of various proportions of highly sulfated maltoheptaose and MMA units. It was revealed that the anti‐HIV activity increased with decreasing proportion of the sulfated oligosaccharide moiety and that a copolymethacrylate having 22 mol % of sulfated maltoheptaose units (DS = 3.0) had a high anti‐HIV activity in the EC₅₀ of 0.3 μg/mL. The blood anticoagulant activity increased slightly from 9 to 18 unit/mg with decreasing proportion of the sulfated maltoheptaose units. These results suggested that the biological activities were influenced strongly by the spatial distance between sulfated oligosaccharide substituents in the polymethacrylate main chain. Distinction and conformation of the oligosaccharide side chains also played an important role. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 789–800, 1999     

Cyclic Voltammetric Study of Some Anti‐Chagas‐Active 1,4‐Dioxidoquinoxalin‐2‐yl Ketone Derivatives

The electrochemical properties of 24 1,4‐dioxidoquinoxalin‐2‐yl ketone derivatives with varying degrees of anti‐Chagas activity were investigated in the aprotic solvent dimethylformamide (DMF) by cyclic voltammetry and first‐derivative cyclic voltammetry. For this group of compounds, the first reduction in DMF was either reversible or quasireversible and consistent with reduction of the N‐oxide functionality to form the radical anion. The second reduction process for these compounds was irreversible under the conditions used. The reduction potentials correlated well with molecular structure. Substitution in the 3‐, 6‐, and 7‐ positions of the quinoxaline ring by electron‐withdrawing substituents directly affected the ease of reduction and improved the biological activities of these compounds, whereas substitution by electron‐donating groups had the opposite effect. The electrochemical results, when combined with previous work on their mechanism of action against Chagas disease and their measured anti‐Chagas activities, indicated that the quinoxaline 1,4‐dioxide system serves as a promising starting point for chemical modifications aimed at improving the T. cruzi activity via a possible bioreduction mechanism.     

Microwave‐assisted Synthesis of Novel 3,4‐Bis‐chalcone‐N‐arylpyrazoles and Their Anti‐inflammatory Activity

A series of 3,4‐bis‐chalcone‐N‐arylpyrazoles 3a‐h was prepared conveniently from diacetyl pyrazoles 2a,b . All reactions were carried out under conventional thermal heating and/or microwave irradiation. The structure of the latter functionally pyrazoles was confirmed under the bases of their IR, mass, ¹H NMR and ¹³C NMR. The X‐ray diffraction of compound 3e not only confirmed the chemical structure of 3a‐h , but also showed the E configuration of their chalcone moieties. Treatment of compound 3e with phenyl hydrazine in presence of acetic acid afforded the tri‐pyrazle 4 . The anti‐inflammatory activity of the newly synthesized compounds was investigated. Some of these compounds showed a moderate activity when compared with indomethacin as a reference drug. The combination between chalcone and pyrazole moieties revealed a variable effect in anti‐inflammatory activity.     

Comparative Study of three Mononuclear Vanadium‐Aromatic 1, 2‐Diol Complexes: Structure,Characterization and Anti‐Proliferating Effects Against Cancer Cells

Three mononuclear vanadium complexes containing aromatic 1, 2‐diols (catechol and naphthalene‐2, 3‐diol) ligands,[V^IVO(cat)₂][1, 3‐HPDA]₂ · CH₃OH ( 1 ), [V^IVO(N‐2, 3‐D)₂][1, 3‐H₂PDA] ( 2 ), and [V^VO₂(N‐2, 3‐D)(1, 3‐HPDA)] · 1, 3‐PDA ( 3 ) (cat = catechol, N‐2, 3‐D = naphthalene‐2, 3‐diol, 1, 3‐PDA = 1, 3‐propanediamine) were synthesized and characterized by X‐ray diffraction, IR and UV/Vis spectroscopy, and cyclovoltammetry. X‐ray analysis reveals that the spatial frameworks of complexes 1 – 3 are all constructed by hydrogen bonds donated by [1, 3‐H_nPDA]ⁿ⁺ (n = 1, 2) cation, forming distinct chain structures. Complexes 1 and 2 are both in the non‐chiral form of VO(L)₂, but 2 crystallizes in the chiral space group (P6₅22), due to the symmetry element of spiral axis, whereas complex 3 contains both enantiomers of chiral VO₂(L₁)(L₂) units, but crystallizes in the non‐chiral space group (P$\bar{1}$ ). The electrochemical behavior of the three complexes is studied in comparison with that of the free ligands. Complex 1 shows a pair of potentials assigned to the redox behavior of vanadium, while complexes 2 and 3 exhibit no such redox potentials. Pharmaceutical screening of complexes 1 – 3 were carried out against three representative cancer cell lines: A‐549 (lung cancer), Bel‐7402 (liver cancer) and HCT (colonic cancer) by MTT [3‐(4, 5‐dimethylthiazoyl‐2‐yl)‐2, 5‐diphenyltetrazolium bromide] assay. The results show that the vanadium‐catechol complex 1 exhibits more obvious anti‐proliferating effects against the three cell‐lines, whereas the two vanadium‐N‐2, 3‐D complexes 2 and 3 basically display no such effects.     

Synthesis and Antiviral Bioactivity of Novel 2‐Substituted Methlthio‐5‐(4‐Amino‐2‐Methylpyrimidin‐5‐yl)‐1,3,4‐Thiadiazole Derivatives

A series of novel 2‐substituted methlthio‐5‐(4‐amino‐2‐methylpyrimidin‐5‐yl‐)‐1,3,4‐thiadiazole derivatives were synthesized, characterized and evaluated for antiviral activities against tobacco mosaic virus (TMV). The preliminary biological results indicated that most compounds exhibit excellent antiviral activity against TMV in vivo. Among these compounds, compounds 9c , 9i , and 9p displayed the similar curative effect against TMV (EC₅₀ = 287.05–322.47 µg/mL) to that of the commercial agent Ningnanmycin (EC₅₀ = 301.83 µg/mL). In particular, compound 9d demonstrated the best curative effect against TMV (EC₅₀ = 266.21 µg/mL), which was better than that of commercial Ningnanmycin.     

Antiviral and Antibacterial Activities of N‐(4‐Substituted phenyl) Acetamide Derivatives Bearing 1,3,4‐Oxadiazole Moiety

In this paper, a series of N‐(4‐substituted phenyl) acetamide derivatives bearing 1,3,4‐oxadiazole moiety were synthesised. Preliminary bioassays revealed that these compounds not only exhibited favourable antiviral activities toward tobacco mosaic virus (TMV) but also demonstrated sustained inhibition activities against plant pathogenic bacteria, including Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri. Among the derivatives, TC ₈ and TC ₂₀ exerted the strongest curative activities against TMV, with half‐maximal effective concentration (EC₅₀) values of 239.5 and 236.2 µg/mL, respectively, which were comparable to that of ningnanmycin (EC₅₀=273.2 µg/mL). Given their simple synthesis, the target compounds can serve as alternative antiviral candidates.     

Synthesis and Anti‐HIV Activity of Triazolo‐Fused 2′,3′‐Cyclic Nucleoside Analogs Prepared by an Intramolecular Huisgen 1,3‐Dipolar Cycloaddition

Triazolo‐fused 2′,3′‐cyclic nucleoside analogs were synthesized by an intramolecular 1,3‐dipolar cycloaddition of nucleoside‐derived azido alkynes in a regio‐ and stereospecific manner. The uracil base in these target compounds was successfully transformed to the corresponding cytosine. The synthesized compounds were examined in a MAGI assay for their anti‐HIV activities, and in a H9 T lymphocytes assay for their cell toxicities.     

Synthesis and Anti‐HIV‐1 Evaluation of New Sonogashira‐Modified Emivirine (MKC‐442) Analogues

The MKC‐442 analogue 6‐(3,5‐dimethylbenzyl)‐5‐ethyluracil substituted with a (propargyloxo)methyl group at N(1) has previously been found highly active against HIV‐1. The C?C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents with higher activity against HIV‐1‐resistant mutants. The syntheses involved Pd‐catalyzed C,C‐coupling reactions, addition of disulfides, and click chemistry on the terminal C?C bond as well as addition of bromine to the so formed internal C?C bonds. Sonogashira coupling were performed with silyl‐derivatized iodobenzyl alcohols which, after deprotection, were oxidized to aldehydes by means of IBX. The isomeric alcohol 37 was obtained in the Sonogashira reaction of propargyl alcohol with the N(1)‐substituted (4‐iodobenzyloxy)methyl derivative of the above mentioned uracil. Compound 37 turned out to be the most effective compound against problematic HIV‐1 mutants. The general observation in the present work is that a combination of alkyne and aryl in the substituent at N(1) leads to highly active compounds against HIV‐1.     

Synthesis,Antimicrobial and Anti‐HIV Activity of Some Novel Benzenesulfonamides Bearing 2,5‐Disubstituted‐1,3,4‐Oxadiazole Moiety

Twelve novel primary ( 4a‐c , 5a‐c ) and secondary ( 4d‐f, 5d‐f ) benzenesulfonamides bearing 2,5‐disubstituted‐1,3,4‐oxadiazole moiety have successfully been prepared by direct chlorosulfonation of phenyl substitutent present on the 2‐position of 5‐mercapto‐1,3,4‐oxadiazoles 2a‐c and their methylhio derivatives 3a‐c using chlorosulfonic acid under anhydrous conditions. Structures of the synthesized compounds were established by their physical and spectral data. Some of the synthesized compounds have been screened in vitro for their antimicrobial and anti‐HIV activity; the results were in accordance with SAR.