Synthesis and evaluation of novel peptidomimetics bearing p-aminobenzoic acid moiety as potential antidiabetic agents.

Aim: Search for a new class of potential antidiabetic agents. Methodology: A series of novel peptidomimetics bearing the p-aminobenzoic acid moiety (TM3-TM6) were designed and synthesized. For all synthetic target molecules, the peroxisome proliferator response element (PPRE) activated activities have been evaluated and the toxicity were computed. Results & discussion: 46 new p-aminobenzoic acid derivatives have been characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). The results of in vitro PPRE-activated activity, molecular docking study and toxicity prediction revealed that these compounds had potential antidiabetic activities and low toxicity. In particular compound 3b had up to 87% PPRE-activated activity compared with pioglitazone. This discovery may provide new insights for finding novel PPRE lead compound.

Chlorophyll-Catalyzed Visible-Light-Mediated Synthesis of Tetrahydroquinolines from N,N-Dimethylanilines and Maleimides.

Natural pigment chlorophyll was used as a green photosensitizer for the first time in a visible-light photoredox catalysis for the efficient synthesis of tetrahydroquinolines from N,N-dimethylanilines and maleimides in an air atmosphere. The reaction involves direct cyclization via an sp3 C-H bond functionalization process to afford products in moderate to high yields (61-98%) from a wide range of substrates with a low loading of chlorophyll under mild conditions. This work demonstrates the potential benefits of chlorophyll as photosensitizer in visible light catalysis.

Enzyme-Catalyzed Asymmetric Domino Thia-Michael/Aldol Condensation Using Pepsin.

The novel catalytic promiscuity of pepsin from porcine gastric mucosa for the asymmetric catalysis of the domino thia-Michael/aldol condensation reaction in MeCN and buffer was discovered for the first time. Broad substrate specificity was tested, and a series of corresponding products were obtained with enantioselectivities of up to 84% ee. This specific catalysis was demonstrated by using recombinant pepsin and control experiments with denatured and inhibited pepsin. The reaction was also shown to occur in the active site by site-directed mutagenesis (the Asp32Ala mutant of pepsin), and a possible mechanism was proposed.

Earthworm is a versatile and sustainable biocatalyst for organic synthesis.

A crude extract of earthworms was used as an eco-friendly, environmentally benign, and easily accessible biocatalyst for various organic synthesis including the asymmetric direct aldol and Mannich reactions, Henry and Biginelli reactions, direct three-component aza-Diels-Alder reactions for the synthesis of isoquinuclidines, and domino reactions for the synthesis of coumarins. Most of these reactions have never before seen in nature, and moderate to good enantioselectivities in aldol and Mannich reactions were obtained with this earthworm catalyst. The products can be obtained in preparatively useful yields, and the procedure does not require any additional cofactors or special equipment. This work provides an example of a practical way to use sustainable catalysts from nature.

Design, synthesis, and biological evaluation of dihydroartemisinin-fluoroquinolone conjugates as a novel type of potential antitubercular agents.

Tuberculosis remains a global public health problem in recent years. To develop novel type of potential antitubercular agents, twelve novel dihydroartemisinin-fluoroquinolone (DHA-FQ) conjugates (three types of molecules) were gradually designed and conveniently synthesized. All the newly synthesized conjugates were well characterized and evaluated against different Mycobacterium tuberculosis strains in vitro. The screening results showed that five DHA-FQ conjugates were active toward M. tuberculosis H37Rv, and compound 3a exhibited the strongest inhibitory activity (MIC=0.0625 µg/mL), which was comparable to the positive control Moxifloxacin and even stronger than Ofloxacin. Conjugates 2a and 3a also displayed comparable activities against various clinically isolated sensitive and resistant M. tuberculosis strains (MIC=0.125-16 µg/mL) to Moxifloxacin. All target compounds possessed selective anti-M. tuberculosis ability. Preliminary structure-activity relationship demonstrated that short linker between DHA and FQ was favorable for strong antitubercular activity. This study provides a new clue for the development of novel antitubercular lead molecules.

[Design, synthesis and PPAR agonist activities of novel L-tyrosine derivatives containing phenoxyacetyl moiety].

The design, synthesis and bioevaluation of a series of novel L-tyrosine derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Four intermediates and twenty L-tyrosine derivatives containing phenoxyacetyl moiety TM1 were synthesized starting from L-tyrosine via four step reactions including the esterification of carboxyl group, phenoxyacetylation of a-amino group, bromoalkylation of phenolic hydroxyl group and then nucleophilic substitution reaction with various heterocyclic amines in 21%-75% overall yield. Subsequently TM1 were hydrolyzed to give sixteen corresponding target compounds TM2 in 77%-99% yield. The chemical structures of the thirty-nine new compounds were identified using 1H NMR, 13C NMR techniques and thirty-five were confirmed by HR-MS techniques. Screening results in vitro showed that the PPAR relative activation activities of the target molecules are weak overall, while compound TM2i reaches 50.01%, which hints that the molecular structures of these obtained compounds need to be modified further.

Design, synthesis and evaluation of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents.

A series of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents were synthesized for the first time and screened for their antimicrobial efficacy against four Gram-positive bacteria, four Gram-negative bacteria and two fungi by two fold serial dilution technique. The bioactive assay indicated that most of the target compounds displayed broad antimicrobial spectrum and good antibacterial and antifungal activities with low MIC values ranging from 0.25 to 2 µg/mL against all the tested strains which exhibited comparable or even better efficiency in comparison with the reference drugs Chloramphenicol, Clinafloxacin and Fluconazole, respectively. Notably, some synthesized clinafloxacin triazoles showed stronger efficacy against methicillin-resistant Staphylococcus aureus than their parent Clinafloxacin.

Synthesis and antidiabetic performance of ß-amino ketone containing nabumetone moiety.

We wish to report the further design and improved synthesis that resulted in two series of target molecules, TM-1 and TM-2, with remarkably simplified structures containing ß-amino ketone of discrete nabumetone moiety. These were obtained via a 'one-pot, two-step, three-component' protocol of Mannich reaction with yield up to 97%. A total of 28 out of 31 new compounds were characterized using (1)H NMR, (13)C NMR, ESI MS and HRMS techniques. Studies on their antidiabetic activities, screened in vitro at 10 µg mL(-1) level, indicate that TM-2 possesses peroxisome proliferator-activated receptor activation and α-glucosidase inhibition activity significantly stronger than that of TM-1, and also that of the series B compounds that were previously synthesized by the group. Analysis of the structure-activity relationship points to the sulfanilamide unit as the most probable potent group of ß-amino ketone and, on the basis of which, a tangible strategy is presented for the development of new antidiabetic drugs.

[Synthesis and PPAR activities of novel phenylacetic acid derivatives containing sulfonamide moiety].

The discovery of high performance leading antidiabetic compounds containing sulfonamide and 4-aminophenylacetic acid moieties is reported. This was achieved by the synthesis of 6 intermediates and subsequently 20 target molecules using 4-aminophenylacetic acid as the starting materials, and through a few synthetic routes aided by multi-step reactions including sulfonylation of amino group, deacylation of amides and esterification of carboxyl group, as well as acylation of amino group. The chemical structures of the twenty-four new compounds were determined using 1H NMR, 13C NMR and HR-MS techniques. Screening in vitro of their peroxisome proliferator-activated receptor (PPAR) activation activities showed weak relative PPAR activation activities to most of the target molecules. However, 4 target molecules exhibit PPAR over 58%, and as high as 81.79% for TM2-i, presenting itself as potent leading compound for antidiabetic drugs. This research also confirms that it is probable to achieve esterification of carboxyl group and deacylation of fatty acid N-phenyl amides concurrently in SOCl2/alcohol solvent system. This provides new synthetic method for the selective reaction within molecules containing both carboxyl and N-aryl amido groups of fatty acids.

[FTIR, FT-Raman and surface enhanced Raman study of S-thyminyl-L-cysteine].

The present paper reports the FT-infrared spectra and FT-Raman spectra of the S-thyminyl-L-cysteine. The optimal concentration of the S-thyminyl-L-cysteine on silver sol is 10(-4) mol L(-1). The interaction of S-thyminyl-L-cysteine with Ag nanoparticles was adsorbed by COO-, NH3+, S, and ring in the tilted way. Amino peak was enhanced in the acidic condition, carboxyl peak was enhanced in alkaline condition. Adsorption of S-thyminyl-L-cysteine on silver nanoparticles was mainly with carboxyl under the acidic condition and with amino under the alkaline condition. Other groups had no change at different pH. Establishment of this adsorption model provided important information and useful reference for further Raman spectra study of PNA, peptides and other biological molecules.

[Synthesis of novel beta-aminoalcohols containing nabumetone moiety with potential antidiabetic activity].

Twenty five new beta-aminoalcohols containing nabumetone moiety were prepared via the reduction of potassium borohydride with a convenient and efficient procedure, starting from beta-aminoketones that have been synthesized by our group. Their chemical structures were determined by IR, MS, 1H NMR, 13C NMR, HR-MS and antidiabetic activities were screened in vitro. Preliminary results revealed that the antidiabetic activity of most beta-aminoalcohols were better than that of the corresponding beta-aminoketones. Although most compounds showed weak antidiabetic activity, the alpha-glucosidase inhibitory activity of compounds 5hd(1) and 5id(2) reached 74.37% and 90.15%, respectively, which were superior to the positive control. The relative peroxisome proliferator-activated receptor response element (PPRE) activity of five compounds were more than 60%, among them compound 5ca possessed the highest activity (112.59%). As lead molecules of antidiabetic agents, compounds 5hd(1), 5id(2) and 5ca deserve further study.

[Study of vibrational spectra of humic substance in soils from the three Gorges Reservoir Area].

The six typical different parts of soils and sediments along the bank of the Three Gorges Reservoir Area (TGRA) were collected, and the humic substance isolated from the six parts of the soils and sediments' samples was separated to humic acid and fulvic acid, purified, and characterized with the combination of the Raman and IR vibrational spectroscopic technologies after cool-dried separation; through assigning the vibrational peaks in each part of the Raman and IR spectra of each sample part, the vibrational characteristics of the structures and the groups that belonged to the molecules of the humic acids and the fulvic acids in the soils and sediments of the TGRA were obtained; the changing features of the groups and structures in the humic acid and the fulvic aicd's molecules from the different soils and sediments in the TGRA were discussed with the environmental impact factors such as soil humic degree, the conditions of different soils conference, using and/or cultivating models and water level fluctuations. From the experimental results, the vibrations about C-O, C-C, and poly-hydrogen bonds dominate in the structures and the groups of each part' humic substance; the active vibration numbers in the upstream are more than in the downstream; the soil's humic degree has great effect on the formation of the humic substances' structures in soil's humic substance; the soil used as agricultural cultivating mode showed higher humic degrees in the upstream parts of the TGRA. The effect of the water level's fluctuation on the formation of the humic acid and fulvic aicd in the sediments of the TGRA is not obvious in the short time.

[Study of the fluorescence characteristics of DOM from the Yangtze River and Jialing River around Chongqing's urban areas].

The fluorescence emission and excitation emission matrix (EEM) technologies were used to characterize the dissolved organic matter (DOM) in the water body of the Yangtze River and Jialing River around the Chongqing urban areas from April to August 2008. Concerning about the accidents of the Wenchuan's Earthquake in May and Tangjiashan Yansaihu's effects in June, and the high water period time in the summer in two months of July and August, from the EEM obtained from each sampling station and time, the composition, distribution and their changing features of the DOM in the two rivers were investigated as combined with the water samples' environmental parameters such as pH, DO, DOC with EEM's fingerprint features, f(450/500) etc; finally the bio-environment behavior effects of the three types of fluorescence peaks were elaborated, where humic-like, fulvic-like, and protein-like from the five sampling stations' EEMs during the five months were given detailed representation. From the experimental results obtained, the fluorescence peaks are mainly composed of two types of fluorophores: humic-like and protein-like in the two rivers around the Chongqing urban areas during the investigation in five months, the protein-like's peaks value in Jialing River is higher than the values in the Yangtze River, and all the fluorescence peaks in the two Rivers' water body decrease more or less after the two Rivers join in Chun Tan sampling station; the protein-like peak is notably higher after the "5 x 12" earthquake period time including May and June and high water period time, which mainly originated from terrestrial sources, but its intensities decreased observably while the water bodies of the two rivers joining together in the Chao Tianmen and Chun Tan's sampling station.

[Synthesis and investigation on antidiabetic activity of 4-(1-aryl-3-oxo-5-phenylpentylamino) benzenesulfonamide].

Searching for new antidiabetic lead compound, 4-(1-aryl-3-oxo-5-phenylpentylamino) benzenesulfonamides were designed and synthesized directly by three component one-pot condensation of 4-phenyl-2-butanone and sulfanilamide with some aromatic aldehydes at an yield of 23%-97%. The chemical structures of the twelve new Mannich bases were confirmed by 1H NMR, 13C NMR, FTIR, ESI-MS and HR-MS. The screening results of antidiabetic activity indicated that most of these title compounds possess alpha-glucosidase inhibitory activity, among which compound le is the strongest one. And compound 11 possesses good peroxisome proliferator-activated receptor response element (PPRE) agonist activity. The structure-activity relationship of these new beta-amino ketones containing benzenesulfonamide unit was also discussed preliminarily.

[Synthesis and alpha-glucosidase inhibitory activity of N-(1,5-diaryl-3-pentone-1-yl)-4-aminobenzoic acid].

In order to find highly active antidiabetic lead compound, sixteen 4-aminobenzoic acid derivatives were designed and synthesized directly through Mannich reaction in the solution of ethanol at 15-35 degrees C with facile method, mild reaction condition and high yield (45%-90%). Fifteen of them are new compounds. Their structures were confirmed by 1H NMR, 13C NMR, IR, ESI-MS and HR-MS. Alpha-glucosidase inhibitory activity of these compounds indicated that most of these compounds possess the activity with the order: 2c > 2b > 2h > 1a > 1f. The structure-activity relationship of these 4-aminobenzoic acid derivatives was also discussed.

[Synthesis and preliminary evaluation of antidiabetic activity of 4-(3-(4-bromophenyl)-3-oxo-1-arylpropylamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide].

Diabetes mellitus is a common metabolic disease with a high and growing prevalence affecting 4% of the population worldwide, the development of safe and effective therapeutic drug is the major thrust for chemists and pharmacists. To search for active antidiabetic lead compound, we designed and synthesized some novel beta-amino ketone derivatives containing sulfamethoxazole moiety directly through Mannich reaction of sulfamethoxazole, 4-bromoacetophenone and some aromatic aldehydes catalyzed by concentrated hydogen chloride or iodine in the solution of ethanol at 24-40 degrees C with convenient operation, mild reaction condition and satisfactory yield (32%-90%). Their chemical structures were characterized by 1H NMR, 13C NMR, MS and HR-MS. Biological activity tests showed that, in the range of low concentration (5-10 microg x mL(-1)), these title compounds to a certain degree possess protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and a-glucosidase inhibitory activity, moreover, some could activate peroxisome proliferator-activated receptor response element (PPRE) moderately. The PPRE agonist activities of seven compounds are almost 40% of that of Pioglitazone (the positive control), compound 12 shows the strongest activity (66.35%) among them. Thus, it was found that some of 4-(3-(4-bromophenyl)-3-oxo-1-arylpropylamino)-N-(5-methyl-isoxazol-3-yl) benzenesulfonamide containing sulfamethoxazole moiety exhibited antidiabetic activity for the first time.

[FTIR, FT-Raman and surface enhanced Raman study of shikimic acid].

The authors reported the FT-infrared, and FT-Raman spectra of shikimic acid in solid state and in saturated liquid state in the present article. The vibrational peaks of each group in the molecular structure of shikimic acid were obtained and assigned, and furthermore, the Raman and IR vibrational shifts of the corresponding groups in the molecular structure of shikimic acid were analyzed and speculated especially. As shikimic acid mixed with silver nanoparticle the SERS-active substrate, and was adsorbed on the surface of the silver nanoparticle, we also obtained the surface enhanced Raman scattering (SERS) spectra of shikimic acid at different concentrations from 1.0 x 10(-1) to 1.0 x 10(-5) mol x L(-1), further more the adsorption state and the adsorption characteristics of shikimic acid, adsorbed on the surface of the silver nanoparticle, were studied and speculated with the SERS method and the surface selective rule together. Strong Raman signals were detected in the experiments and each group's vibrations in the molecular structure of shikimic acid were resolved with the combination of FT-infrared and FT-Raman spectroscopy. From the experiment data, the ideal optimized concentrations range is lower than 1 x 10(-3) mol x L, among which we could obtain better SERS spectra. Still, the experimental results suggested that the groups in the molecule structure of shikimic acid, such as COO-, OH-, CH2 and so on, can interact and be absorbed tightly with the surface of silver nanoparticle, and this interaction and absorption were mainly through the SERS charge transfer process mechanism of hydroxyl and carboxyl, and SERS electromagnetic process mechanism of methylene and hypomethyl together with the surface of silver nanopartical. The vibrations of alkene's C=C bond on the ring of cyclohexene in the molecule structure of shikimic showed no obvious enhancement in SERS spectra, which indicated that alkene's C=C bond on the ring of cyclohexene in the molecule structure of shikimic acid had no effective interaction and adsorption on the surface of silver nanoparticle according to the surface selective rule.

[Study on adsorption of nonpolar R-side amino acids on silver nanoparticles by FT-SERS].

The adsorption orientation and adsorption characteristics of aliphatic-nonpolar amino acids represented by L-methionine on silver nanoparticles were studied by FT-surface-enhanced Raman spectroscopy (FT-SERS) method with different pH and concentrations. According to the experiments, in order to get the best FT-SERS effects, the optimal concentration range of the L-methionine on silver sol is between 10(-3) mol x L(-1)-10(-4)(mol x L(-1). The FT-SERS effects and adsorption model change with pH; The SERS are poor when pH is near the isoelectric point or over 11 or 3. The interaction of L-methionine with Ag nanoparticles is the physical and chemical adsorption by NH3, COO-, S, which could also be effected by pH. From the results and previous reports on this aspect, the general rules of the adsorption model and the orientation of the aliphatic-nonpolar amino acids on silver nanoparticles were speculated, which would be useful for the study of amino acids, protein, peptide, enzyme etc.

[Fluorescence resonance energy transfer quenching method for determination of arsenic with acridine orange-rhodamine B].

A new method for the determination of trace arsenic was developed by using fluorescence resonance energy transfer from acridine orange (AO) to rhodamine B (RB). It was found that under the condition of lambda(ex)/lambda(em) = 470/580 nm, effective energy transfer could occur between AO and RB in the dodecyl benzene sodium sulfonate solution. The fluorescence intensity of RB was diminished by molybdoarsenide which was formed by the reaction of arsenic (V) with molybdate in sulfuric acid medium. The detection limit of this method was 2. 56 microg x L(-1). This method was used for the determination of trace arsenic in tea. The range of determination for arsenic was 0.01-0.25 mg x L(-1). The relative standard deviation for the determination of arsenic was 0.48%-0.64%. The recoveries for the addition of 0.01-0.03 mg x L(-1) arsenic were 98%-103%. The method has been applied to the determination of arsenic with satisfactory results.