Synthesis and evaluation of 4-(1,3,4-oxadiazol-2-yl)-benzenesulfonamides as potent carbonic anhydrase inhibitors.

Human Carbonic anhydrase (hCA) I and II are crucial targets for anti-acute mountain sickness. Twenty-one 4-(1,3,4-oxadiazol-2-yl) benzenesulfonamides were synthesized and screened against these two isoforms. The results illustrated that 5c, 5g, 5h, 5k were more potent against both hCA I and II than clinical drug AAZ. In particular, the value of compound 5c with hCA I (18.08 nM) was over 84-fold more than of AAZ with hCA I. The data of docking simulations were also in accord with the tendency of inhibitive activities. Furthermore, compound 6h, the methanesulfonate of 5h, showed better anti-hypoxia activity than AAZ in vivo, making it interesting lead compound.

Optimization of activity localization of quinoline derivatives: Design, synthesis, and dual evaluation of biological activity for potential antitumor and antibacterial agents.

A novel of quarternary amine around a quinolinium iodide combined with even number alkyl chain were prepared in a several step in moderate yield starting from malonic ester and benzo[d][1,3]dioxol-5-amine. All of the active structure compounds were identified by nuclear magnetic resonance (NMR), such as 1H NMR, 13C NMR, infrared radiation (IR), high resolution mass spectrometry (HR-MS) and Carlo Erba Instruments CHNS-O EA1108 spectra analysis. With regard to the anticancer properties, the in vitro cytotoxicity against three human cancer cell lines (A-549, Hela and SGC-7901) were evaluated. The antibacterial properties against two human bacterial strains, Escherichia coli (ATCC 29213) and Staphylococcus aureus (ATCC 8739), along with minimum inhibitory concentration (MIC) values were evaluated. The target compounds, 5-12, exhibited significant antitumor and antibacterial activity, of which compound 12 was found to be the most potent derivative with IC50 values of 5.18 ± 0.64, 7.62 ± 1.05, 17.59 ± 0.41, and 54.45 ± 4.88 against A-549, Hela, SGC-7901, and L-02 cells, respectively, stronger than the positive control 5-FU and MTX. Furthermore, compound 12 had the most potent inhibitory activity. The MIC of this compound against Escherichia coli (ATCC 29213) and Staphylococcus aureus (ATCC 8739) was 3.125 nmol·mL-1, which was smaller than that of the reference agents, amoxicillin and ciprofloxacin.

N-Quinary heterocycle-4-sulphamoylbenzamides exert anti-hypoxic effects as dual inhibitors of carbonic anhydrases I/II.

Acute mountain sickness (AMS) affects approximately 25-50% of newcomers to high altitudes. Two human carbonic anhydrase isoforms, hCA I and II, play key roles in developing high altitude illnesses. However, the only FDA-approved drug for AMS is acetazolamide (AAZ), which has a nearly 100 times weaker inhibitory activity against hCA I (Ki = 1237.10 nM) than hCA II (Ki = 13.22 nM). Hence, developing potent dual hCA I/II inhibitors for AMS prevention and treatment is a critical medical need. Here we identified N-quinary heterocycle-4-sulphamoylbenzamides as potent hCA I/II inhibitors. The newly designed compounds 2b, 5b, 5f, 6d, and 6f possessed the desired inhibitory activities (hCA I: Ki = 16.95-52.71 nM; hCA II: Ki = 8.61-18.64 nM). Their hCA I inhibitory capacity was 22- to 76-fold stronger than that of AAZ. Relative to the control group for survival in a mouse model of hypoxia, 2b and 6d prolonged the survival time of mice by 21.7% and 29.3%, respectively, which was longer than those of AAZ (6.5%). These compounds did not display any apparent toxicity in vitro and in vivo. In addition, docking simulations suggested that the quinary aromatic heterocycle groups stabilised the interaction between hCA I/II and the inhibitors, which could be further exploited in structure optimization studies. Hence, future functional studies may confirm 2b and 6d as potential clinical candidate compounds with anti-hypoxic activity against AMS.

Synthesis and Evaluation of the Antitumor Activity of Novel 1-(4-Substituted phenyl)-2-ethyl Imidazole Apoptosis Inducers In Vitro.

Novel imidazole derivatives were designed, prepared, and evaluated in vitro for antitumor activity. The majority of the tested derivatives showed improved antiproliferative activity compared to the positive control drugs 5-FU and MTX. Among them, compound 4f exhibited outstanding antiproliferative activity against three cancer cell lines and was considerably more potent than both 5-FU and MTX. In particular, the selectivity index indicated that the tolerance of normal L-02 cells to 4f was 23-46-fold higher than that of tumor cells. This selectivity was significantly higher than that exhibited by the positive control drugs. Furthermore, compound 4f induced cell apoptosis by increasing the protein expression levels of Bax and decreasing those of Bcl-2 in a time-dependent manner. Therefore, 4f could be a potential candidate for the development of a novel antitumor agent.

Synthesis, activity evaluation, and pro-apoptotic properties of novel 1,2,4-triazol-3-amine derivatives as potent anti-lung cancer agents.

In this study, a series of 4,5-bis(substituted phenyl)-4H-1,2,4-triazol-3-amine compounds was designed, synthesised, and evaluated to determine their potential as anti-lung cancer agents. According to the results of screening of lung cancer cell lines A549, NCI-H460, and NCI-H23 in vitro, most of the synthesised compounds have potent cytotoxic activities with IC50 values ranging from 1.02 to 48.01 µM. Particularly, compound 4,5-bis(4-chlorophenyl)-4H-1,2,4-triazol-3-amine (BCTA) was the most potent anti-cancer agent, with IC50 values of 1.09, 2.01, and 3.28 µM against A549, NCI-H460, and NCI-H23 cells, respectively, meaning many-fold stronger anti-lung cancer activity than that of the chemotherapeutic agent 5-fluorouracil. We also explored the effects of BCTA on apoptosis in lung cancer cells by flow cytometry and western blotting. Our results indicated that BCTA induced apoptosis by upregulating proteins BAX, caspase 3, and PARP. Thus, the potential application of compound BCTA as a drug should be further examined.

Boc-protected 1-(3-oxocycloalkyl)ureas via a one-step Curtius rearrangement: mechanism and scope.

1-(3-Oxocyclobutyl) carboxylic acid (4a) was converted into N-Boc-protected 1-(3-oxocyclobutyl) urea (5a), a key intermediates for the preparation of agonists of metabotropic glutamate receptor 5, in one-step when treated with diphenyl phosphoryl azide and triethylamine in tert-butanol. The mechanism of the reaction involves a nucleophilic addition of the in situ generated tert-butyl carbamate to the isocyanate intermediate. This reaction is applicable to other 1-(3-oxocycloalkyl) carboxylic acids but not to linear γ-keto carboxylic acids.

Preparation and Interfacial Properties of Hydroxyl-Containing Polyimide Fibers.

Developing polyimide (PI) fibers with excellent interfacial adhesion and high mechanical properties for the PI fiber-reinforced polymer matrix composites (PFRPs) industry has been challenging. In this work, 4,4'-diamino-(1,1'-biphenyl)-3,3'-diol (HAB) diamine was introduced into the rigid molecular chains, and the high-performance PI fibers, presenting an interfacial shear strength (IFSS) value of 46.33 MPa, tensile strength of 2.62 GPa, and modulus of 100.15 GPa, were successfully manufactured when the content of HAB in mixed diamines was 30 mol %. Fourier transform infrared (FTIR) spectroscopy identified the presence of intermolecular H-bonding interactions, and 2D small-angle X-ray scattering indicated that the introduction of HAB moiety contributed to reducing the radii of microvoids in the fibers, which were considered to be the key factors leading to a significant enhancement in the mechanical properties of the fibers. X-ray photoelectron spectroscopy (XPS) and the static contact angle intuitively illustrated that the synthetic fiber surface contained active hydroxyl groups. The IFSS value of PI fiber/epoxy resin composites (PI/EPs) was 56.47 MPa when the content of HAB reached 70 mol %. Failure morphologies confirmed that the interfacial adhesion of PI/EPs was enhanced owing to the surface activity of PI fibers. Consequently, this study provides an effective strategy to the long-standing problems of high mechanical performances and poor surface activity for traditional PI fibers used in the PFRPs industry.

Design, Synthesis, and Dual Evaluation of Quinoline and Quinolinium Iodide Salt Derivatives as Potential Anticancer and Antibacterial Agents.

A series of novel quinoline and quinolinium iodide derivatives were designed and synthesized to discover potential anticancer and antibacterial agents. With regard to anticancer properties, in vitro cytotoxicities against three human cancer cell lines (A-549, HeLa and SGC-7901) were evaluated. The antibacterial properties against two strains, Escherichia coli (ATCC 29213) and Staphylococcus aureus (ATCC 8739), along with minimum inhibitory concentration (MIC) values were evaluated. The target alkyliodine substituted compounds exhibited significant antitumor and antibacterial activity, of which compound 8-((4-(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-propyl-[1,3]dioxolo[4,5-g]quinolin-5-ium (12) was found to be the most potent derivative with IC50 values of 4.45±0.88, 4.74±0.42, 14.54±1.96, and 32.12±3.66 against A-549, HeLa, SGC-7901, and L-02 cells, respectively, stronger than the positive controls 5-FU and MTX. Furthermore, compound 12 had the most potent bacterial inhibitory activity. The MIC of this compound against both E. coli and S. aureus was 3.125 nmol ⋅ mL-1 , which was smaller than that against the reference agents amoxicillin and ciprofloxacin.

Characterization of the anticonvulsant activity of doxepin in various experimental seizure models in mice.

In this paper, the anticonvulsant characteristics of doxepin were evaluated in numerous experimental seizure models, including maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, isoniazid (ISO)-, 3-mercaptopropionic acid (3-MP)-, bicuculline (BIC)-, thiosemicarbazide (THIO)-, and strychnine (STR)-induced seizures. In addition, the acute adverse-effect profile of doxepin with respect to impairment of motor coordination was assessed with a mouse rotarod test. The evaluation of the time-course and dose-response relationships for doxepin provided evidence that the peak maximum anticonvulsant activity and acute adverse effects occurred 5 min after intraperitoneal (ip) administration. The results also revealed that doxepin had excellent anticonvulsant activity against maximal electroshock-induced seizures in mice with a median effect value (ED(50)) of 6.6 mg/kg. The assessment of acute adverse effects in the rotarod test revealed that doxepin induced acute neurotoxicity, and its median toxic dose (TD(50)) was 26.4 mg/kg. Additionally, doxepin showed anticonvulsant activity in several chemically-induced seizure models, including ISO, 3-MP, BIC, and THI. Based on this study, we can conclude that the antidepressant drug doxepin may be useful for treatment of depression in patients with epilepsy due to its short time to peak maximum anticonvulsant activity after ip administration (5 min) and remarkable anticonvulsant activity (6.6 mg/kg).

Synthesis of 8-alkoxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline-1-ones and evaluation of their anticonvulsant properties.

A series of 8-alkoxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline-1-one derivatives were synthesized using 7-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and the subcutaneous pentylenetetrazole test (sc-PTZ), and their neurotoxicities were measured by the rotarod neurotoxicity test (Tox). The tests demonstrated that 8-hexyloxy-4,5-dihydro-[1.2.4]triazole[4.3-a]quinoline-1-one (4e) and 8-heptyloxy-4,5-dihydro-[1,2,4] triazole[4,3-a]quinoline-1-one (4f) were the most potent anticonvulsants, with 4e having ED50 values of 17.17 mg/kg and 24.55 mg/kg and protective index (PI = TD50/ED50) values of 41.9 and 29.3 in the MES and sc-PTZ tests, respectively, and 4f having ED50 values of 19.7 mg/kg and 21.2 mg/kg and PI values of 36.5 and 33.9 in the MES and sc-PTZ tests, respectively. The PI values of 4e and 4f were many fold better than that of the marketed drugs phenytoin, carbamazepine, phenobarbital and valproate, which have PI values in the range of 1.6-8.1 in the MES test and < 0.22-5.2 in the sc-PTZ test. Structure-activity relationships were also discussed.

[FTIR spectroscopic studies of hydration effect on the molecular structure of polyether urethane].

The interaction between water molecules and the polar groups in linear polyether urethane was studied by FTIR and subtraction spectroscopy technique. Direct proofs of the combining of water molecule and carbonyl group were obtained. The reorganizations of the ether linkage, carbamate, and carbon-hydrogen chain after hydration were also observed. These results suggest that the FTIR and subtraction spectroscopy technique could be a useful tool to investigate the hydration mechanism of polymer materials.

[Structural study on the transparency of cross-linked polyester polyurethane].

The polyurethane material with cross-linked structure was synthesized using half pre-polymerization method. IR, UV-Vis, TEM and XRD methods, and physical properties measurements indicate that different moulding temperatures influence the apparent transparence of polyurethane and abrasive performance, and the nature of these changes is related to the conditions of processand chemical reaction which lead to gradual micro-phase separation of the polyurethane molecules with different compositions, resulting in the domain-forming with the size of sub-micro-, micro- and even more than ten micro-meters. Such domains aggregate one another to form particles with different shapes and complicated structures. The increase in the amount and size of these heterogeneous particles, distributed in the medium of transparent polyurethane, is the main cause that brings on an opaque appearance of polyurethane.

[The studies on YCl3/PEU system by rheology analysis and FTIR].

FTIR spectroscopy and rheology analysis were applied to study the YCl3/PEU system. It is apparent that modification with lanthanide complexes such as yttrium leads to a slight increase in viscosity of the polyether urethane solution. The authors conclude that this may be due to the interaction between the lanthanide ions and the polar group in urethane.A new band appears at 1650 cm(-1) in the infrared spectra of the YCl3/PEU system, which corresponds to the new carbonyl structure formed through the coordination with yttrium cations. The dynamic rheological behaviors of the solutions demonstrate the interaction furthermore. A higher molecular weight formed with the higher concentration of the lanthanide ions in this DMF solution. And this could be an effective method to characterize the structure of the polymer solutions.

Facile Synthesis of Spirocyclic Lactams from ß-Keto Carboxylic Acids.

A facile synthesis of spirocyclic lactams starting from ß-keto carboxylic acids via a one-pot cascade reaction involving a Curtius rearrangement and an intramolecular nucleophilic addition of the enol carbon to the isocyanate intermediate is reported. The same conditions have also been used for the generation of fused cyclic lactams with similar good yields. The synthetic value of this method has been demonstrated by efficient synthesis of tetracyclic spirolactam 8 and pentacyclic spirolactam 9.

[The interaction between La and polyurethane system].

A series of polyether polyurethane (PU)-LaCl3 composites with different lanthanum contents were prepared. DSC results indicate that LaCl3 promotes phase transition behavior of the LaCl3/PU composites, which causes the endothermic peak at 11.58 degrees C to disappear. FTIR spectroscopy demonstrates that significant variation can be observed. The peak at 1633 cm(-1) attributed to carbonyl vibration and the peak at 3311 cm(-1) attributed to N-H stretching band moves to 1647 cm(-1) and 3355 cm(-1), respectively, when LaCl3 is introduced into the PU system. A new band (-200 cm(-1)) assigned to the La-O band was observed, and the far IR result provided a direct evidence of the coordination between La3+ ion and C=O group of PU system.

Synthesis of 2´-hydroxy-4´-isoprenyloxychalcone derivatives with potential antidepressant-like activity.

A series of 2´-hydroxy-4´-isoprenyloxychalcone derivatives was synthesized and evaluated for its antidepressant- like activity using the FST and TST. All compounds exhibited the potential antidepressant-like activity in the FST and the TST through intraperitoneal injection. Among them, compounds 4i, 4l and 4n exhibited more potent antidepressant- like activity at a dose of 10 mg/kg. And, compounds 4i, 4l and 4n were also adequately absorbed in mice after oral administration at a dose of 30 mg/kg. In the 5-HT induced head-twitch test and yohimbine induced mortality test, compound 4i could increase the head-twitch and rise mortality in mice. The results suggested that the antidepressant effects of compound 4i may be related to via the serotonergic and noradrenergic system.

Synthesis and evaluation of antibacterial activity of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline derivatives.

In this study, a series of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline derivatives was synthesized and tested for their antibacterial activity against various bacterial strains. Most of the compounds exhibited potential antibacterial activity against gram-negative and gram-positive bacteria. Compound 7p (7-heptyloxy-4,5-dihydro-imidazo[1,2-a]quinoline) was found to be the most potent inhibitor. The minimum inhibitory concentration (MIC) of compound 7p against Escherichia coli was 0.5 µg/mL, better than that of reference agent ciprofloxacin and amoxicillin. Furthermore, compound 7p exhibited a modest activity against several gram-negative bacterial strains at a dose range of 2-64 µg/mL.

N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice.

The antidepressant-like effects of N-palmitoylethanolamide (PEA), a putative endocannabinoid, was investigated in mice using the tail suspension test (TST) and the forced swimming test (FST). In TST, PEA (10, 20, and 40 mg/kg) produced a statistically significant reduction in immobility (50, 32, and 34%, respectively, vs. the control group), whereas fluoxetine (20 mg/kg) reduced immobility by 38%. In FST, PEA (5, 10, and 20 mg/kg) produced a statistically significant reduction in immobility (15, 21, and 36%, respectively), whereas fluoxetine (20 mg/kg) reduced immobility by 18%. Moreover, PEA (20 mg/kg) did not significantly change motor activity in a spontaneous behavioral test. In conclusion, PEA (dose range of 5-40 mg/kg) administered orally reduced immobility in TST and FST, comparable to the antidepressant effect of fluoxetine, and had no effect on spontaneous activity in mice.

Synthesis and anti-inflammatory activity evaluation of some novel 6-alkoxy(phenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine derivatives.

Starting from phthalic anhydride, several new 6-alkoxy(phenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine derivatives were synthesized as potent anti-inflammatory agent. The study showed that the compounds 6h (6-(2-chlorophenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine) and 6s (6-(4-aminophenoxy)-[1,2,4] triazolo[3,4-a]phthalazine-3-amine) exhibited the highest anti-inflammatory activity (81% and 83% inhibition, respectively, at 0.5 h after i.p. administration) which were slightly more potent than the reference drug Ibuprofen (61%). Furthermore, the peak activity of 6h and 6s was observed at the 3 h after p.o. administration, and they exhibited stronger anti-inflammatory activity than Ibuprofen at the dose of 50 mg/kg at the peak time.

Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various experimental seizure models in mice.

This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The neurotoxicity of QUAN-0808 was investigated using the rotarod neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED(50) = 6.8 mg/kg) and lower neurotoxicity (median toxic dose, TD(50) = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED(50) = 24 mg/kg) against MES-induced seizure with low neurotoxicity (TD(50) > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.