Design, synthesis, biological evaluation, structure-activity relationship, and toxicity of clinafloxacin-azole conjugates as novel antitubercular agents.

Based on the advantages of azole molecules and fluoroquinolone drugs, we designed and synthesized 34 clinafloxacin-azole conjugates using fragment-based drug design and drug combination principles. The in vitro activities of the synthesized conjugates against Mycobacterium tuberculosis (H37Rv), Hela cell as well as Gram-positive and Gram-negative bacteria were assayed. The bioassay results revealed that most of the target molecules had anti-tuberculosis (anti-TB) activity, of which 14 compounds had very strong anti-TB activity [minimum inhibitory concentration (MIC) < 2 µM]. In addition, the compounds with strong activity towards H37Rv had weak activity towards Gram-negative and Gram-positive bacteria, showing obvious selectivity towards H37Rv. Predicted toxicity data indicated that 27 molecules were less toxic or equivalent to that of the original drug (clinafloxacin). Especially, it is demonstrated that compound TM2l exhibited the strongest anti-TB activity (MIC = 0.29 µM), low antibacterial activity, negligible toxicity, and good drug-likeness values, which can be considered as an ideal lead molecule for future optimization.

Design, synthesis, and evaluation of novel l-phenylglycine derivatives as potential PPARγ lead compounds.

In accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l-phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator-activated receptor gamma (PPARγ) activated activity, α-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105.04% at 10 µg·mL-1 compared with the positive control pioglitazone, with 100% activity). Therefore, M5 was selected as the hit compound from which the TM3 and TM4 series of compounds were further designed and synthesized. Based on the PPRE relative activities of TM3 and TM4, we discovered another new molecule, TM4h, which had the strongest PPRE relative activity (120.42% at 10 µg·mL-1). In addition, the concentration-dependent activity of the highly active compounds was determined by assaying their half-maximal effective concentration (EC50) values. The molecular physical parameter calculation and the molecular toxicity prediction were used to theoretically evaluate the lead-likeness and safety of the active compounds. In conclusion, we identified a potential PPARγ lead molecule and developed a tangible strategy for antidiabetic drug development.

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.

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 evaluation of the antibacterial enhancement activities of amino dihydroartemisinin derivatives.

Artemisinin (ART) and its derivatives artesunate (AS), dihydroartemisinin (DHA) are a group of drugs containing a sesquiterpene lactone used to treat malaria. Previously, AS was shown to not have antibacterial activity but to significantly increase the antibacterial activities of ß-lactam antibiotics against E. coli. Herein, molecular docking experiments showed that ART, AS and DHA could dock into AcrB very well, especially DHA and AS; both DHA and AS had the same docking pose. The affinity between AS and AcrB seemed weaker than that of DHA, while the succinate tail of AS, which was like a "bug", could extend in the binding pocket very well. Imitating the parent nucleus of DHA and the succinate tail of AS, twenty-one DHA derivatives 4a-u were designed and synthesized. Among them, seventeen were new compounds. The synergistic effects against E. coli AG100A/pET28a-AcrB showed among the new structures 4k, 4l, 4m, 4n, and 4r exhibited significant synergism with ß-lactam antibiotics although they had no direct antibacterial activities themselves. The bacterial growth assay showed that only 4k in combination with ampicillin or cefuroxime could totally inhibit bacterial growth from 0 to 12 h, demonstrating that 4k had the best antibacterial enhancement effect. In conclusion, our results provided a new idea and several candidate compounds for antibacterial activity enhancers against multidrug resistant E. coli.

[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.

[Levels and inhalation exposure analysis of polybrominated diphenyl ethers in atmosphere of Shenzhen].

OBJECTIVE: Objective Concentrations and proliles of 7 polybrominated diphenyl ethers (PBDEs) compounds in ambient air in Shenzhen city were analyzed, and inhalation exposure amount for local resident was concluded firstly domesticly. METHODS: 7 polybrominated diphenyl ethers compounds (PBDEs) (BDE-28, BD-E-47, BDE-99, BDE-100, BDE-153, BDE-154, BDE-183) in ambient air (including gas phase and particle phase ) were determined by isotope dilution high-resolution gas chromatography/high-resolution double-focusing magnetic mass spectrometer (HRGC/ HRMS) with High volume active air sampler for 11 sampling sites in 6 administrative district in Shenzhen. Furthermore, the inhalation exposure amount for local resident was calculated and concluded using concentration of PBDEs, respiratory rate and gas exchange in the air ratio in Alveolar. RESULTS: The average concentration of PBDEs in atmosphere samples was 29.03 pg/m, ranged from 8.28-168.86 pg/m, the PBDEs pollution level as higher in rain season than that in dry season. The predominant PBDEs congeners measured in the two periods were BDE-47 and BDE-99, accounted for more than 31 and 16 percent of total concentration, respectively. While the specific profile was found in the dry season, the seven monomer distribution proportion tended to be equal, especially BDE-183 accounted for 17 percent of total concentration. Inhalation exposure amount for local adults and children was 4.72 pg/kg and 10.74 pg/kg respectively. CONCLUSION: he levels of PBDEs in atmosphere in Shenzhen are higher than that in United Kingdom, South Korea, Osaka and Kyoto in Japan, however it is lower than the reported levels of Guangzhou and Beijing. Children's breathing exposure amount is higher than that in adults, this circumstances should be paid more attention. Furthermore, the present study provides the important basic data of PBDEs pollution level in Shenzhen and Inhalation exposure amount for local residents firstly.

Cyanidin-3-O-glucoside ameliorates cadmium induced uterine epithelium proliferation in mice.

Cadmium (Cd) is an environmental pollutant and endocrine disrupter, abundantly present in water, food, and soil. Accumulation of Cd in the body can negatively affect female reproduction; especially the uterus is exceptionally sensitive to the toxic actions of Cd. The anthocyanin cyanidin-3-O-glucoside (C3G) is a naturally occurring phenolic compound in fruits and plants that can antagonize the toxic effects of Cd. This capacity makes C3G a possible candidate to prevent Cd-induced female infertility. The present study aimed to investigate: 1) whether C3G intake could prevent Cd-induced female reproductive toxicity, and 2) the underlying mechanisms responsible for this protective effect. The results of our study indicated that Cd exposure did not affect ovarian function, but induced hypertrophy of the uterine endometrium. Oral intake of C3G markedly reduced the effects of Cd exposure on the thickness of the uterine epithelium cells. Transcriptomic analysis of the endometrium revealed that C3G intake had anti-estrogenic effects, attenuating Cd-induced endometrial epithelial cell proliferation by inhibiting estrogen-responsive genes, enhancing epithelial progesterone receptor expression, and regulating Klf4 expression. The current findings implicate that C3G has the potential to be used as a dietary supplement based on its capacity to intervene in Cd-induced female reproductive toxicity.

[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.

[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 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.

[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 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.

Cyanidin-3-O-glucoside restores spermatogenic dysfunction in cadmium-exposed pubertal mice via histone ubiquitination and mitigating oxidative damage.

Cadmium (Cd) is an environmental contaminant found in soil, water, and food, and can cause oxidative stress and male reproductive damage. During puberty, the male reproductive system is very vulnerable to interference, however, the dysregulation of Cd on spermatogenesis in this period is ambiguous. The anthocyanin cyanidin-3-O-glucoside (C3G) is phytochemical rich in plants and fruits and has been shown to have remarkable anti-oxidant activity, making it an ideal nutrient for nutritional intervention. By modeling Cd-induced damage in male pubertal mice and feeding with C3G, we demonstrated that the C3G could rescue the amount and activity of sperm predominantly. Furthermore, C3G showed partial resistance to Cd-induced histone modification during spermiogenesis and prevented oxidative damage of the DNA in the sperm nucleus. Additionally, C3G mitigated the oxidative stress of testis to achieve the level coinciding with the control group. Meanwhile, Cd-induced mitochondrial apoptosis of sperm cells was reduced significantly via the MAPK signaling pathway in the presence of C3G. Collectively, our findings can offer a potential intervention for combating Cd-induced reproductive damage during puberty by taking anthocyanin as a dietary supplement.

[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.