Binding and Assembly of a Benzotriazole Cavitand in Water.

A water-soluble cavitand bearing a benzotriazole upper rim was prepared and characterized. It exists as a dimeric velcraplex in D2 O, but forms host-guest complexes with hydrophobic and amphiphilic guests. Alkanes (C5 to C10), cyclic ketones (C6-C10), cyclic alcohols (C6-C8) and various amphiphilic guests form 1 : 1 cavitand complexes. A cyclic array of hydrogen bonds, bridged by solvent/water (D2 O) molecules, stabilizes the vase conformation of the complexes. With longer alkanes (C12-C15), symmetrical dialkyl amine, urea and phosphate, 2 : 1 host:guest capsules are formed. Computations indicate that additional waters on the upper rim create a self-complementary hydrogen-bonding pattern for capsule formation.

Hydrophobic and Metal-Coordinated Confinement Effects Trigger Recognition and Selectivity.

We report the synthesis and characterization of a new water-soluble cavitand 1. The container features 2-aminobenzimidazole panels at the "rim" and pyridiniums at the "feet". In the solid state, a single-crystal X-ray structure of the organic-soluble precursor 2 showed a stable vase form. The structure is stabilized by hydrogen-bonded bridges between adjacent panels through solvents and ions. In aqueous solution, binding of hydrophobic and amphiphilic guest molecules to 1 was investigated using 1H NMR. Alkanes, alcohols, acids, diols, and diacids formed 1:1 host-guest complexes, and the guest conformations were deduced from characteristic chemical shift changes. In the presence of [Pd(ethylenediamine)(H2O)2·2NO3], cavitand 1 formed a complex incorporating two metals. The metal-coordinated cavitand also bound hydrophobic linear alkanes and difluorobenzene isomers in aqueous medium. The metallo-cavitand showed shape and size selectivity and was used to separate o-difluorobenzene from its isomers as observed by 19F NMR spectroscopy. The primary amino function of the cavitands offers possibilities for further elaboration to covalent clusters of these container compounds.

Binding selectivity and separation of p-functionalized toluenes with a metallo-cavitand in water.

A metallo-cavitand (1-2Pd) showed unprecedented binding selectivity and sequestration of p-functionalized toluene isomers in water. The host-guest complexation was studied using 1H and COSY NMR methods and xylene-isomer complexes were examined by using DFT calculations. A liquid-liquid extraction scheme was developed for the separation of p-functionalized toluenes.

WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice.

The global prevalence of nonalcoholic steatohepatitis (NASH) increases incredibly. NASH ends up to advanced liver disease, which is highly threatening to human health. Currently, treatment of NASH is very limited. Acetyl-CoA carboxylases (ACC1/ACC2) are proved as effective drug targets for NASH. We aimed to develop novel ACC inhibitors and evaluate their therapeutic value for NASH prevention. ACC inhibitors were obtained through structure-based drug design, synthesized, screened from ACC enzymatic measurement platform and elucidated in cell culture-based assays and animal models. The lipidome and microbiome analysis were integrated to assess the effects of WZ66 on lipids profiles in liver and plasma as well as gut microbiota in the intestine. WZ66 was identified as a novel ACC1/2 inhibitor. It entered systemic circulation rapidly and could accumulate in liver. WZ66 alleviated NASH-related liver features including steatosis, Kupffer cells and hepatic stellate cells activation in diet-induced obese mice. The triglycerides (TGs) and other lipids including diglycerides (DGs), phosphatidylcholine (PC) and sphingomyelin (SM) were decreased in WZ66-treated mice as evidenced by lipidome analysis in livers. The lipids profiles in plasma were also altered with WZ66 treatment. Plasma TG were moderately increased, while the activation of SREBP1c was not detected. WZ66 also downregulated the abundance of Allobaculum, Mucispirillum and Prevotella genera as well as Mucispirillum schaedleri species in gut microbiota. WZ66 is an ideal lead compound and a potential drug candidate deserving further investigation in the therapeutics of NASH.

Synthesis and anti-hepatocellular carcinoma activity of novel O2-vinyl diazeniumdiolate-based nitric oxide-releasing derivatives of oleanolic acid.

Considering that high levels of nitric oxide (NO) exert anti-cancer effect and the derivatives of oleanolic acid (OA) have shown potent anti-cancer activity, new O2-vinyl diazeniumdiolate-based NO releasing derivatives (5a-l, 11a-l) of OA were designed, synthesized, and biologically evaluated in the present study. These derivatives could release different amounts of NO in liver cells. Among them, 5d, 5i, 5j, 11g, 11h, and 11j released more NO in SMMC-7721 cells and displayed stronger proliferative inhibition against SMMC-7721 and HepG2 cells than OA and other tested compounds. The most active compound 5j showed almost 20-fold better solubility than OA in aqueous solution, released larger amounts of NO in liver cancer cells than that in normal ones, and exhibited potent anti-hepatocellular carcinoma activity but little effect on the normal liver cells. The inhibitory activity against the cancer cells was significantly diminished upon addition of an NO scavenger, suggesting that NO may contribute, at least in part, to the activity of 5j.

Synthesis and blocking activities of a new class of α1-adrenoceptor antagonists.

Finding effective chemotherapeutic agents for clinical use is a long-lasting goal in medicinal chemistry. In this study, we report a new class of α1-adrenoceptor (α1-AR) antagonists. Specifically, we describe the synthesis and the blocking activities toward α1-AR of 7-(2-hydroxypropoxy)-3,4-dihydroisoquinolin-1(2H)-one 1 and its structurally perturbed analogs 2-11 that were designed according to the principle of bioisosterism. Their structures were identified with IR, (1) H NMR, MS, HRMS and elemental analysis. The blocking activities of compounds 1-11 were evaluated on isolated rat anococcygeus muscles. The results indicated that these compounds showed moderate to good activities. Among them, compound 1 exhibited the highest activity that was comparable to those of known α1-AR antagonists tamsulosin and DDPH (1-(2,6-dimethylphenoxy)-2-(3,4-di- methoxyphenylethylamino)propane hydrochloride) and thus may be exploitable as a lead compound for the discovery of promising α1-AR antagonists.

Synthesis and biological evaluation of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups as potential hypoglycemic agents.

A novel class of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups were designed and synthesized. The target compounds were assayed for the effects on the insulin release of isolated rat pancreatic islets and the glucose transport in adipocytes of rats. Some of them exhibited high potency. Compound 10 also had potent antiplatelet activity and showed an excellent property to protect collagen-epinephrine-induced mice mortality as well as plasma glucose-lowering activity in vivo. The preliminary pharmacological profile of compound 10 showed that it might be useful in the treatment of diabetics with cardiovascular and nephropathy complications.

[Synthesis and antibacterial activity of imidazothiadiazoles and heterocyclic-amine Mannich-base hydrochloride].

To optimize the synthetic method and antibacterial activity of fused heterocyclic thiadiazole compounds, cyclocondensation of 2-(4-methoxyphenyl)-5-amino-1,3,4-thiadiazole (2) with alpha-chloro-4-chloro acetophenone (3) resulted in a key intermediate (4), 6 -(4-chlorophenyl)-2-(4-methoxyphenyl)-imidazo-[2,1-b][1,3,4]thiadiazole, which was carried out an nucleophilic substitution with substituted piperazine to give the corresponding free bases of piperazine (5a-5c), then followed by Mannich reaction with heterocyclicamines and formaldehyde to yield the corresponding Mannich bases, (1a-11) as respective hydrochloride salts. The structures were confirmed by IR, 1H NMR, MS and elemental analysis and the antibacterial activities in vitro of fifteen newly synthesized compounds were also tested against Gram positive bacteria and Gram negative bacteria with the standard 2-fold agar dilution method. The antibacterial results showed that the introduction of a polar group resulted in the enhancement of antibacterial activity in vitro. Thus, the structures of these fused compounds could further be investigated.

Design and synthesis of tetrahydroisoquinoline derivatives as potential multidrug resistance reversal agents in cancer.

Exploration for new MDR-modulator utilizing tetrahydroisoquinoline as scaffold disclosed 6,7-dimethoxy-1-(3,4-dimethoxy)benzyl-2-(N-n-octyl-N'-cyano)guanyl-1,2,3,4-tetrahydroisoquinoline (7) as a readily accessible medicinal lead. Compound 7 possessed potent MDR reversal activity in the range of the reference compound verapamil, and had not cardiovascular activity compared to verapamil.

Halomonas caseinilytica sp. nov., a halophilic bacterium isolated from a saline lake on the Qinghai-Tibet Plateau, China.

A halophilic, Gram-negative bacterial strain, designated AJ261T, which was isolated from a soil sample from a salt lake on the Qinghai-Tibet Plateau, was subjected to a polyphasic taxonomic study. The isolate grew optimally in the presence of 3-5 % NaCl and used various carbohydrates as sole carbon and energy sources. The genomic DNA G+C content was 63.0 mol%. The predominant fatty acids were C18 : 1omega7c, C16 : 0 and C12 : 0. A phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate had the highest sequence similarity with respect to type strains of Halomonas elongata (98.2 %), Halomonas eurihalina (98.1 %) and Halomonas halmophila (97.2 %). The DNA-DNA relatedness of strain AJ261T with respect to H. elongata NBRC 15536T, H. eurihalina CGMCC 1.2318T and H. halmophila DSM 5349T was 42, 25 and 26 %, respectively. Overall, the phenotypic, genotypic and phylogenetic results demonstrate that strain AJ261T represents a novel species within the genus Halomonas, for which the name Halomonas caseinilytica is proposed. The type strain is AJ261T (=CGMCC 1.6773T =JCM 14802T).

[Synthesis and antitumor activity of C3 heterocyclic-substituted fluoroquinolone derivatives (I): ciprofloxacin aminothiodiazole Schiff-bases].

To discover a novel antitumor lead compound derived from fluoroquinolone, C3 carboxyl group of ciprofloxacin (1) was replaced with heterocyclic ring to form cyclopropyl fluoroquinolone aminothiadiazole scaffold (2), then reacted with aromatic aldehydes to give the Schiff bases compounds (3a-3j). The structures of new compounds were characterized by element analysis and spectral data, and their in vitro antitumor activity against SMMC-7721, HL60 and L1210 cell lines was evaluated by MTT assay via the respective IC50 values. The bioactive assay showed that eleven thiadiazole-substituted ciprofloxacin derivatives displayed potential cytotoxicity against the tested cancer cell lines, where the IC50 values of compounds 3d and 3f reached micromolar concentration. Therefore, the C3 carboxyl group of fluoroquinolone is not necessary to antitumor activity. Functionally modified heterocycle-substituted fluoroquinolone as potent antitumor lead compound is valuable for further study.

4-[2-(3,4-Dimethoxy-phenethyl-amino)prop-oxy]-2-methoxy-benzamide.

The title compound, C(21)H(28)N(2)O(5), has two intra-molecular N-H⋯O hydrogen bonds. Inter-molecular N-H⋯O hydrogen bonds [graph-set motif R(2) (2)(8)] give rise to a dimer. Weak N-H⋯N hydrogen bonds between neighboring dimers further extend the crystal structure, which exhibits an infinite chain motif.

Halomonas saccharevitans sp. nov., Halomonas arcis sp. nov. and Halomonas subterranea sp. nov., halophilic bacteria isolated from hypersaline environments of China.

Three strains of Gram-negative, aerobic, neutrophilic and halophilic bacteria were isolated from samples of a salt lake on the Qinghai-Tibet Plateau and a subterranean saline well in the Si-Chuan Basin of China. These isolates, designated AJ275(T), AJ282(T) and ZG16(T), were investigated using a polyphasic approach. Based on 16S rRNA gene sequence analysis, the isolates could be affiliated to the genus Halomonas. Genomic DNA G+C contents were 65.9 mol% for AJ275(T), 56.7 mol% for AJ282(T) and 57.6 mol% for ZG16(T). The results of DNA-DNA hybridizations, fatty acid analysis and physiological and biochemical tests allowed the isolates to be differentiated genotypically and phenotypically from closely related species. It is proposed that strains AJ275(T) (=CGMCC 1.6493(T)=JCM 14606(T)=LMG 23976(T)), AJ282(T) (=CGMCC 1.6494(T)=JCM 14607(T)=LMG 23978(T)) and ZG16(T) (=CGMCC 1.6495(T)=JCM 14608(T)=LMG 23977(T)) represent the type strains of three novel species in the genus Halomonas: Halomonas saccharevitans sp. nov., Halomonas arcis sp. nov. and Halomonas subterranea sp. nov., respectively.

[Synthesis and antibacterial activity of 3-(4-piperazin-1-yl-phenyl)-s-triazolo [3,4-b] [1,3,4] thiadiazole hydrochlorides].

To study the synthetic method and antibacterial activity of water-soluble fused heterocyclic compounds containing piperazine group, the nucleophilic substitution of 3-(4-chlorophenyl)-6-substituted-s-triazolo-[3, 4-b] [1, 3, 4] thiadiazoles (2a - n) with piperazine in the presence of phase transfer catalyst TBAI afforded 3-(4-piperazin-1-yl-phenyl)-6-substituted-s-triazolo [3, 4-b] [1, 3, 4] thiadiazole and then followed by acid treatment afforded 3-(4-piperazin-1-yl-phenyl)-6-substituted-s-triazolo [ 3, 4-b] [1, 3, 4] thiadiazole hydrochlorides (3a - n). Twenty-eight new compounds were synthesized and their structures were confirmed by IR, 1H NMR, MS and element analysis. The in vitro antibacterial activities of all newly synthesized compounds were tested against Gram positive bacteria and Gram negative bacteria with the standard 2-fold agar dilution method. Fourteen title compounds exhibited potential antibacterial activities in vitro. The structures of these compounds needed to be further optimized.

Halorubrum arcis sp. nov., an extremely halophilic archaeon isolated from a saline lake on the Qinghai-Tibet Plateau, China.

A Gram-negative, aerobic, neutrophilic and extremely halophilic archaeon (strain AJ201(T)), isolated from Ayakekum salt lake on the Qinghai-Tibet Plateau, was investigated by a polyphasic approach. The DNA G+C content of strain AJ201(T) was 65.7 mol%. The major polar lipid profile and phylogenetic analysis based on 16S rRNA gene sequences supported the allocation of the strain to the genus Halorubrum. The results of DNA-DNA hybridizations and physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain AJ201(T) from closely related species. Therefore, strain AJ201(T) represents a novel species of the genus Halorubrum, for which the name Halorubrum arcis sp. nov. is proposed. The type strain is strain AJ201(T) (=CGMCC 1.5343(T)=JCM 13916(T)).

[Genetic analysis of the br gene in halophilic archaea isolated from Xingjiang region].

Some novel members of extremely halophilic Archaea, strain AJ11, AJ12 and AJ13, were isolated from Aularz Lake located in Altun Mountain National Nature Reserve of Xinjiang Uygur Autonomous Region in China. Partial DNA fragments encoding a bacteriorhodopsin (BR) as well as for 16S rRNA of isolated strains were amplified by PCR and their DNA sequences were determined subsequently. On the basis of homology and phylogenetic analysis about 16S rDNA, it was considered that the isolated strains formed a microbiological population are the members of genus Natrinema. The results of genetic analysis, such as GC content, transition/transversion (Ti/Tv) rate ratios, synonymous substitution rates (Ks), indicated that the br fragments with high level of genetic divergence are faced with both purifying selection and bias mutation pressure. The study provides the base for using of species and BR proteins resources.

[Synthesis and vascular relaxing activity of arecoline derivatives coupled with nitric oxide donors].

AIM: To search for potential anti-atherosclerosis drugs with vascular relaxation activity, a series of agonists of endothelial targets were designed and synthesized. METHODS: Coupling N-methyl-1,2, 3,6-tetrahydrapyridine ring system with 3,4-dibenzenesulfonyl-1,2,5-oxadiazole-2-oxide through esterification or amidation, a series of arecoline derivatives containing NO donors were designed and synthesised. RESULTS: A novel series of compounds structurally related to arecoline have been prepared, the proposed structures of eighteen new compounds were established by IR, 1H NMR, MS spectroscopy and elemental analysis. The effects of the target compounds on the vasodilation activity were tested in the isolated preparation of mice thoratic aorta. CONCLUSION: This preliminary pharmacological tests showed that the candidates have good vasodilation activities and were worthy to be intensively studied.

[Synthesis and antibacterial activity of 3-(4-amino-5-methyl-s-triazol-3-sulfanyl)-1-phenyl-propan-1-one O-(5-substituted phenyl-[1,3,4] oxadiazol-2-methyl)-oximes].

AIM: To study the synthetic method and antibacterial activity of amino-heterocyclic compounds coupled oxime-ether group. METHODS: The treatment of 4-amino-3-methyl-5-mercapto-s-triazole (3) with beta-chlorophenyl-propanone to form amino-s-triazole sulfanylphenyl-propanone (4) sequentially followed by oximation with hydroxyl-amine to produce the oximes (5) and etherification with various oxadiazole chloromethanes (6a - j) to yield the title compounds (1a - j). The in vitro antibacterial activities of all newly synthesized compounds were tested against Gram positive bacteria and Gram negative bacteria with the standard 2-fold agar dilution method. RESULTS: Twelve new compounds including two intermediates were synthesized and their structures were confirmed by IR, 1H NMR, MS and elemental analyses. The ten title compounds exhibited the potential antibacterial activities in vitro. CONCLUSION: Theses compounds should be optimized.

[Synthesis and antibacterial activity of 3-(5-substituted phenyl-[1,3,4] oxadiazole-2-yl-methylenethio)-5-pyridin-3-yl-[1,2,4] triazole-4-yl-amines].

AIM: To study on synthesis and antibacterial activity evaluation of polyheterocycles. METHODS: The condensation of 4-amino-3-pyridin-3-yl-4H-[1,2,4] triazole-5-thiol with 2-chloromethyl-5-substituted phenyl-[1,3,4] oxadiazoles gave the corresponding title heterocycle amines, and the in vitro antibacterial activity was primarily evaluated by the method of cup-plate diffusion solution. RESULTS: Twelve novel compounds were synthesized, and their structures were confirmed by IR, 1H NMR, MS and element analysis. Biological screening results demonstrated that most of the compounds prepared showed good antibacterial activity. CONCLUSION: Oxadiazoles incorporting pyridyl triazole ring may be a pharmacophor structure in the molecule for developing antibacterial candidate drugs.

[Synthesis and antibacterial activity of 2-(3-pyridyl)-5-([(5-aryl-1,3,4-oxadiazol-2-yl) methylene]thio)-1,3,4-oxadiazoles].

AIM: Studies on synthesis and antibacterial activity of new heterocycles. METHODS: The cyclocondensation of [(3-pyridyl)-1,3,4-oxadiazol-2-yl] thio acetic acid with various aroyl hydrazines in the presence of POCl3 and xylene gave the corresponding titled compounds, and the in vitro antibacterial activity was primarily evaluated by the method of cupplate diffusion solution. RESULTS: Sixteen novel titled compounds were synthesized, their structures were confirmed by IR, 1HNMR, MS and elemental analysis. Biological screening results demonstrated that most of the compounds prepared displayed potential antibacterial activity. CONCLUSION: Oxadiazoles incorporting pyridyl oxadiazole ring may be usefully antibacterial candidate drugs.