Efficient and Stable NIR-II Phosphorescence of Metallophilic Molecular Oligomers for In Vivo Single-Cell Tracking and Time-Resolved Imaging.

Molecular phosphorescence in the second near-infrared window (NIR-II, 1000-1700 nm) holds promise for deep-tissue optical imaging with high contrast by overcoming background fluorescence interference. However, achieving bright and stable NIR-II molecular phosphorescence suitable for biological applications remains a formidable challenge. Herein, we report a new series of symmetric isocyanorhodium(I) complexes that could form oligomers and exhibit bright, long-lived (7-8 µs) phosphorescence in aqueous solution via metallophilic interaction. Ligand substituents with enhanced dispersion attraction and electron-donating properties were explored to extend excitation/emission wavelengths and enhanced stability. Further binding the oligomers with fetal bovine serum (FBS) resulted in NIR-II molecular phosphorescence with high quantum yields (up to 3.93 %) and long-term stability in biological environments, enabling in vivo tracking of single-macrophage dynamics and high-contrast time-resolved imaging. These results pave the way for the development of highly-efficient NIR-II molecular phosphorescence for biomedical applications.

[Compound Amino Acid Capsule (8-11) combined with L-carnitine for the treatment of asthenospermia].

OBJECTIVE: To observe the clinical effect of combined application of Compound Amino Acid Capsule (8-11) (CAAC8-11) and L-carnitine (LC) in the treatment of idiopathic asthenospermia (IAS), and to explore its possible therapeutic mechanism. METHODS: Based on the principle of double-blind and control, we selected 120 cases of IAS meeting the diagnostic criteria of asthenospermia in the WHO Manual for the Examination and Processing of Human Semen (5th Ed) and randomly divided them into three groups of an equal number: CAAC8-11 + LC, LC control and blank control, the former given CAAC8-11 in addition to LC oral liquid, and the latter two given LC oral liquid and life intervention, respectively, all for 12 weeks. We collected semen samples from all the patients before and after treatment, and examined perm motility, the contents of neutral α- glucosidase (NAG) and reactive oxygen species (ROS), sperm DNA fragmentation index (DFI), and the expression of the Nrf2 protein. RESULTS: Compared with the baseline, the total sperm motility was significantly improved in the IAS patients after treated with CAAC8-11 + LC (ï¼»27.50 ± 0.77ï¼½% vs ï¼»32.50 ± 0.74ï¼½%, P < 0.05) or LC only (ï¼»27.60 ± 0.66ï¼½% vs ï¼»30.90 ± 0.70ï¼½%, P < 0.05), dramatically higher in the CAAC8-11 + LC than in the LC and blank control groups (P < 0.01). The content of NAG in the epididymis was remarkably increased after treatment in the CAAC8-11 + LC than in the LC and blank control groups (ï¼»23.90 ± 0.56ï¼½ vs ï¼»21.20 ± 0.49ï¼½ and ï¼»16.80 ± 0.42ï¼½ mU, P < 0.05), so was the expression of Nrf2 (P < 0.05), while the ROS level was markedly decreased in the former than in the latter two groups (ï¼»81.60 ± 2.50ï¼½ vs ï¼»88.50 ± 2.50ï¼½ and ï¼»88.70 ± 2.40ï¼½ µg/ml, P < 0.05). CONCLUSION: CAAC8-11 + LC has a good clinical effect on asthenospermia, with no adverse reactions, which may be attributed to its ability to regulate the high expression of Nrf2, decrease the production of ROS and reduce the damage of oxidative stress to sperm motility.

How to rectify the convex coronal imbalance in patients with unstable dystrophic scoliosis secondary to type I neurofibromatosis: experience from a case series.

BACKGROUND: There was a paucity of valid information on how to rectify the convex coronal imbalance effectively in dystrophic scoliosis secondary to Type I neurofibromatosis (DS-NF1), while postoperative inadvertent aggravation of CCI occurred regularly resulting in poor patient satisfaction. We aimed to identify the risk factors for persistent postoperative CCI in DS-NF1, and to optimize the coronal rebalancing strategies based on the lessons learned from this rare case series. METHODS: NF1-related scoliosis database was reviewed and those with significant CCI (> 3 cm) were identified, sorted and the outcomes of surgical coronal rebalance were analyzed to identify the factors being responsible for failure of CCI correction. RESULTS: CCI with dystrophic thoracolumbar/lumbar apex was prone to remain uncorrected (7 failure cases in 11) when compared to those with thoracic apex (0 failure cases in 4) (63.6% vs. 0.0%, p = 0.077). Further comparison between those with and without post-op CCI showed a higher correction of main curve Cobb angle (65.9 ± 9.1% vs. 51.5 ± 37.3%, p = 0.040), more tilted instrumentation (10.3 ± 3.6° vs. 3.2 ± 3.1°, p = 0.001) and reverse tilt and translation of upper instrumented vertebra (UIV) to convex side (8.0 ± 2.3° vs. -3.4 ± 5.9°, p < 0.001; 35.4 ± 6.9 mm vs. 12.3 ± 13.1 mm, p = 0.001) in the uncorrected imbalanced group. Multiple linear regression analysis revealed that △UIV translation (pre- to post-operation) (ß = 0.832; p = 0.030) was significantly correlated with the correction of CBD. CONCLUSION: Thoracolumbar/lumbar CCI in dystrophic scoliosis was prone to suffer high risk of persistent post-op CCI. Satisfying coronal rebalance should avoid UIV tilt and translation to the convex side, tilted morphology of instrumentation and over correction maneuvers for main curve, the upper hemi-curve region in particular.

Could screw/hook insertion at the apical vertebrae with rib head dislocation effectively retract the corresponding rib head from spinal canal in dystrophic scoliosis secondary to type 1 neurofibromatosis?

BACKGROUND: Rib head dislocation (RHD) in dystrophic scoliosis of type 1 neurofibromatosis (DS-NF1) is a unique disorder caused by skeletal dystrophy and scoliotic instability. No particular surgical manipulation is mentioned in the literature to instruct the spine surgeons to effectively obtain more migration of the dislocated rib head without resection. The present study aimed to investigate the effectiveness of screw/hook insertion at vertebrae with RHDs on the retraction of penetrated rib head from spinal canal. METHODS: 37 neurologically intact patients with DS-NF1 and concomitant 53 RHDs undergoing scoliosis surgery without rib head excision were retrospectively reviewed. We used pre and postoperative whole-spine radiographs to determine the Cobb angle and the vertebral translation (VT), and the CT scans to evaluate the intraspinal rib length (IRL) and rib-vertebral angle (RVA). The dislocated ribs were assigned into two groups according to the presence of screw/hook insertion at vertebrae with RHD: screw/hook group and non-screw/hook group. RESULTS: 37 dislocated ribs with screws/hooks insertion at corresponding vertebrae were assigned into the screw/hook group and the remaining 16 dislocated ribs consisted of the non-screw/hook group. In the screw/hook group, the correction rates of Cobb angle and VT were significantly higher than the non-screw/hook group after surgery (58.7 ± 16.0% vs. 30.9 ± 12.4%, p = 0.003; 61.8 ± 18.8% vs. 35.1 ± 16.6%, p = 0.001; respectively). Similarly, more correction rates of IRL and RVA were found in the screw/hook group than the non-screw/hook group (63.1 ± 31.3% vs. 30.1 ± 20.7%, p = 0.008; 17.6 ± 9.7% vs. 7.2 ± 3.6%, p = 0.006; respectively). Multiple linear regression analysis revealed that the correction rates of Cobb angle, VT and RVA contributed significantly to correction of IRL (ß = 0.389, 0.939 and 1.869, respectively; p = 0.019, 0.001 and 0.002, respectively). CONCLUSION: Screw/hook insertion at dystrophic vertebrae with RHDs contributed significantly to the degree of retraction of penetrated rib head from spinal canal. This effectiveness is mediated by more corrections of VT and RVA.

Bioleaching Performance of Titanium from Bauxite Residue Under a Continuous Mode Using Penicillium Tricolor.

The present study performed a continuous mode of bioleaching to investigate the leaching efficiency of Titanium (Ti) from bauxite residue using Penicillium Tricolor at between 4% and 12% pulp densities during a 120-day running. Obtained results of the current study showed that increased pulp density led to a decrease in biomass, dissolved oxygen, and amount of leaching Ti as well as an increase in pH value. Further, it was found that efficiency of bioleaching can be enhanced by increasing the rate of aeration, retention time, and concentration of carbon source. However, it was also evident that, at high pulp density, excessive agitation did not give an expected leaching efficiency but a collapse of biomass. In addition, results of the present study showed that the maximum leaching amount of Ti was 3202 mg/L with a corresponding leaching ratio of 50.35% during the whole bioleaching process. Moreover, it was noted that the biomass showed a significant negative correlation with the pH value and dissolved oxygen. However, the biomass showed a significant positive correlation with leaching amount of Ti and thus indicate that microbial metabolic activities are the uppermost factor affecting the continuous leaching performance.

Finite element analysis of the kinematic coupling effect of the joints around talus when Ponseti manipulation.

BACKGROUND: Little information was obtained from the published papers about the kinematic coupling effect between tarsal bones during Ponseti manipulation. The aim was to explore the kinematic coupling effect of the joints around talus, to investigate the kinematic rhythm and coupling relationship of tarsal joints; to clarify the pulling effect on medial ligament of the ankle during the process of Ponseti manipulation. METHODS: The model of foot and ankle was reconstructed from the Chinese digital human girl No.1 (CDH-G1) image database. Finite element analysis was applied to explore the kinematic coupling effect of the joints around talus. The distal tibia and fibula bone and the head of talus were fixed in all six degrees of freedom; outward pressure was added to the first metatarsal head to simulate the Ponseti manipulation. Kinematic coupling of each tarsal joint was investigated using the method of whole model splitting, and medial ligament pulling of the ankle was studied by designing the model of medial ligament deletion during the Ponseti manipulation. RESULTS: All the tarsal joints produced significant displacement in kinematic coupling effect, and the talus itself produced great displacement in the joint of ankle. Quantitative analysis revealed that the maximum displacement was found in the joints of talonavicular (12.01mm), cuneonavicular (10.50mm), calcaneocuboid (7.97mm), and subtalar(6.99mm).The kinematic coupling rhythm between talus and navicular, talus and calcaneus, calcaneus and cuboid, navicular and cuneiform 1 were 1:12, 1:7, 1:2 and 1:1.6. The results of ligaments pulling showed that the maximum displacement was presented in the ligaments of tibionavicular (mean 27.99mm), talonavicular (21.03mm), and calcaneonavicular (19.18 mm). CONCLUSIONS: All the tarsal joints around talus were involved in the process of Ponseti manipulation, and the strongest kinematic coupling effect was found in the joints of talonavicular, subtalar, calcaneocuboid, and cuneonavicular. The ligaments of tibionavicular, talonavicular, and calcaneonavicular were stretched greatly. It was suggested that the method of Ponseti management was a complex deformity correction processes involved all the tarsal joints. The present study contributed to better understanding the principle of Ponseti manipulation and the pathoanatomy of clubfoot. Also, the importance of cuneonavicular joint should be stressed in clinical practice.

Aggregation Enhanced Responsiveness of Rationally Designed Probes to Hydrogen Sulfide for Targeted Cancer Imaging.

Activatable molecular probes hold great promise for targeted cancer imaging. However, the hydrophobic nature of most conventional probes makes them generate precipitated agglomerate in aqueous media, thereby annihilating their responsiveness to analytes and precluding their practical applications for bioimaging. This study reports the development of two small molecular probes with unprecedented aggregation enhanced responsiveness to H2S for in vivo imaging of H2S-rich cancers. The subtle modulation of the equilibrium between hydrophilicity and lipophilicity by N-methylpyridinium endows these designed probes with the capability of spontaneously self-assembling into nanoprobes under physiological conditions. Such probes in an aggregated state, rather than a molecular dissolved state, show NIR fluorescence light up and photoacoustic signals turn on upon H2S specific activation, allowing in vivo visualization and differentiation of cancers based on differences in H2S content. Thus, our study presents an effective design strategy which should pave the way to molecular design of optimized probes for precision cancer diagnostics.

Tumor microenvironment-activated nanosystems with selenophenol substituted BODIPYs as photosensitizers for photodynamic therapy.

NIR-light-absorbing photosensitizers with the capability of selective localization and activation in tumor regions are of great importance for practical photodynamic therapy (PDT). Here, selenophenol substituted BODIPYs were designed and synthesized as new photosensitizers for PDT. One of these obtained BODIPYs, IBSeOV, possesses an intense and low energy absorption with a high singlet oxygen quantum yield (ΦΔ = 60%). Considering manganese dioxide (MnO2) nanosheets as versatile nanocarriers in cancer theranostics, nanosystem IBSeOV/MnO2 was then fabricated to furnish tumor environment selective activation. Such designed nanoplatform allowed for GSH-controllable 1O2 production and exhibited low cytotoxicity in dark but good photocytotoxicity to cancer cells. The in vivo antitumor outcome suggested the high treatment efficiency of IBSeOV/MnO2 for tumor therapy.

DLX1, a binding protein of beta-catenin, promoted the growth and migration of prostate cancer cells.

Several studies have indicated the involvement of DLX1 in the progression of prostate cancer. However, the functions of DLX1 in the prostate cancer and the underlying molecular mechanism remains largely unknown. In this study, we have shown that DLX1 was up-regulated in the prostate clinical samples. DLX1 promoted the growth, migration and colony formation of prostate cancer cells by activating beta-catenin/TCF signaling. DLX1 interacted with beta-catenin and enhanced the interaction between beta-catenin and TCF4. Taken together, this study demonstrated that DLX1 exerted the oncogenic roles on the prostate cancer by activating beta-catenin/TCF signaling.

Hydrogen Sulfide-Activatable Second Near-Infrared Fluorescent Nanoassemblies for Targeted Photothermal Cancer Therapy.

Near-infrared (NIR)-II fluorescence agents hold great promise for deep-tissue photothermal therapy (PTT) of cancers, which nevertheless remains restricted by the inherent nonspecificity and toxicity of PTT. In response to this challenge, we herein develop a hydrogen sulfide (H2S)-activatable nanostructured photothermal agent (Nano-PT) for site-specific NIR-II fluorescence-guided PTT of colorectal cancer (CRC). Our in vivo studies reveal that this theranostic Nano-PT probe is specifically activated in H2S-rich CRC tissues, whereas it is nonfunctional in normal tissues. Activation of Nano-PT not only emits NIR-II fluorescence with deeper tissue penetration ability than conventional fluorescent probes but also generates high NIR absorption resulting in efficient photothermal conversion under NIR laser irradiation. Importantly, we establish NIR-II imaging-guided PTT of CRC by applying the Nano-PT agent in tumor-bearing mice, which results in complete tumor regression with minimal nonspecific damages. Our studies thus shed light on the development of cancer biomarker-activated PTT for precision medicine.

Theranostic Nanoplatform with Hydrogen Sulfide Activatable NIR Responsiveness for Imaging-Guided On-Demand Drug Release.

NIR light responsive nanoplatforms hold great promise for on-demand drug release in precision cancer medicine. However, currently available systems utilize "always-on" photothermal transducers that lack target specificity, and thus inaccurately differentiate tumors from normal tissues. Developed here is a theranostic nanoplatform featuring H2 S-mediated in situ production of NIR photothermal agents for imaging-guided and photocontrolled drug release. The system targets H2 S-rich cancers. This nanoplatform shows H2 S-activatable NIR-II emission and NIR light controllable release of the drug Camptothecin-11. Upon administering the system to HCT116 tumor-bearing mice, the tumor is greatly suppressed with minimal side effects, arising from the synergy of the cancer-specific and NIR light activated therapy. This theranostic nanoplatform thus sheds light on precision medicine with guidance through NIR-II imaging.

Quercetin protects against chronic prostatitis in rat model through NF-κB and MAPK signaling pathways.

BACKGROUND: Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a common disease of urology, of which the pathogenesis and therapy remain to be further elucidated. Quercetin has been reported to improve the symptoms of CP/CPPS patients. We aimed to verify the therapeutic effect of quercetin on CP/CPPS and identify the mechanism responsible for it. METHODS: A novel CP/CPPS model induced with Complete Freund Adjuvant in Sprague Dawley rats was established and the prostates and blood specimens were harvested for further measurement after oral administration of quercetin for 4 weeks. RESULTS: Increased prostate index and infiltration of lymphocytes, up-regulated expression of IL-1ß, IL-2, IL-6, IL-17A, MCP1, and TNFα, decreased T-SOD, CAT, GSH-PX, and increased MDA, enhanced phosphorylation of NF-κB, P38, ERK1/2, and SAPK/JNK were detected in CP/CPPS rat model. Quercetin was identified to ameliorate the histo-pathologic changes, decrease the expression of pro-inflammatory cytokines IL-1ß, IL-2, IL-6, IL-17A, MCP1, and TNFα, improve anti-oxidant capacity, and suppress the phosphorylation of NF-κB and MAPKs. CONCLUSIONS: Quercetin has specific protective effect on CP/CPPS, which is mediated by anti-inflammation, anti-oxidation, and at least partly through NF-κB and MAPK signaling pathways.

Association between braced curve behavior by pubertal growth peak and bracing effectiveness in female idiopathic scoliosis: a longitudinal cohort study.

BACKGROUND: Pre-pubertal idiopathic scoliosis (IS) is associated with high risk of bracing ineffectiveness. Integrated multidimensional maturity assessments are useful but complex to predict the high-risk occurrence of curve progression. This study is designed to provide a simple screening method for brace effectiveness by determining whether or not the braced curve behavior at growth spurt, being defined as variations in Cobb angle velocity (AV) at peak height velocity (PHV), can be a new factor predictive of brace outcome prescribed before PHV. METHODS: This is a retrospective study of a series of 35 IS girls with simplified skeletal maturity score no more than 3 at initiation of bracing treatment and followed up through the growth spurt until brace weaning or surgery. Serial Cobb angle and maturity indicators involving height velocity, Risser sign, triradiate cartilage, simplified skeletal maturity score and distal radius and ulna classification were assessed and patients were stratified into either a positive or negative category based on a positive or negative value of AV at PHV. Comparisons were made between the positive and negative AV groups, as well as the failed and successful bracing groups, using independent sample T test and crosstab analysis. Logistic regression analysis was used to identify the predictive factors of failed brace treatment. RESULTS: Brace treatment prescribed before PHV was found to have an overall failure rate of 57.1% and a surgical rate of 45.7%. Negative AV at PHV accounting for 54.3% of the recruited patients were associated with lower brace failure rate (36.8% vs. 81.2%, p = 0.016) and surgical rate (21.1% vs. 75.0%, p = 0.002). Patients in the failed bracing group showed higher ratio of thoracic curve (80.0% vs. 26.7%,p = 0.002) and higher AV at growth peak (2.3 ± 9.1 vs. -6.5 ± 11.4°/yrs., p = 0.016). The logistic regression analysis revealed that positive AV at PHV (OR = 9.268, 95% CI = 1.279-67.137, p = 0.028) and thoracic curve type (OR = 13.391, 95% CI = 2.006-89.412, p = 0.007) were strong predictive factors of ineffective brace treatment initiated before PHV. CONCLUSIONS: Sustained curve correction following bracing despite early onset and rapid pubertal growth was strongly predictive of effective brace control of scoliosis.

Imaging of Colorectal Cancers Using Activatable Nanoprobes with Second Near-Infrared Window Emission.

Fluorescent probes in the second near-infrared window (NIR-II) allow high-resolution bioimaging with deep-tissue penetration. However, existing NIR-II materials often have poor signal-to-background ratios because of the lack of target specificity. Herein, an activatable NIR-II nanoprobe for visualizing colorectal cancers was devised. This designed probe displays H2 S-activated ratiometric fluorescence and light-up NIR-II emission at 900-1300 nm. By using this activatable and target specific probe for deep-tissue imaging of H2 S-rich colon cancer cells, accurate identification of colorectal tumors in animal models were performed. It is anticipated that the development of activatable NIR-II probes will find widespread applications in biological and clinical systems.

Near-infrared fluorescent dyes with large Stokes shifts: light generation in BODIPYs undergoing excited state intramolecular proton transfer.

Novel BODIPYs undergoing excited state intramolecular proton transfer are reported. The molecules afford NIR emission with a large Stokes shift and possess a free hydroxyl unit that is easy to functionalize, allowing the dyes to be exploited as a valuable scaffold in probe design.

[Induction of robust senescence-associated secretory phenotype in mouse NIH-3T3 cells by mitomycin C].

Senescence-associated secretory phenotype (SASP) is often a concomitant result of cell senescence, embodied by the enhanced function of secretion. The SASP factors secreted by senescent cells include cytokines, proteases and chemokines, etc, which can exert great influence on local as well as systemic environment and participate in the process of cell senescence, immunoregulation, angiogenesis, cell proliferation and tumor invasion, etc. Relative to the abundance of SASP models in human cells, the in vitro SASP model derived from mouse cells is scarce at present. Therefore, the study aimed to establish a mouse SASP model to facilitate the research in the field. With this objective, we treated the INK4a-deficient mouse NIH-3T3 cells and the wildtype mouse embryonic fibroblasts (MEF) respectively with mitomycin C (MMC), an anticarcinoma drug which could induce DNA damage. The occurring of cell senescence was evaluated by cell morphology, ß-gal staining, integration ratio of EdU and Western blot. Quantitative RT-PCR and ELISA were used to detect the expression and secretion of SASP factors, respectively. The results showed that, 8 days after the treatment of NIH-3T3 cells with MMC (1 µg/mL) for 12 h or 24 h, the cells became enlarged and the ratios of ß-gal-positive (blue-stained) cells significantly increased, up to 77.4% and 90.4%, respectively. Meanwhile, the expression of P21 protein increased and the integration ratios of EdU significantly decreased (P < 0.01). Quantitative RT-PCR detection showed that the mRNA levels of several SASP genes, including IL-6, TNF-α, IL-1α and IL-1ß increased evidently. ELISA detection further observed an enhanced secretion of IL-6 (P < 0.01). On the contrary, although wildtype MEF could also be induced into senescence by MMC treatment for 12 h or 24 h, embodied by the enlarged cell volume, increased ratios of ß-gal-positive cells (up to 71.7% and 80.2%, respectively) and enhanced expression of P21 protein, the secretion of IL-6 displayed no significant change. Our study indicated that, although MMC could induce senescence in both mouse NIH-3T3 cells and wildtype MEF, only senescent NIH-3T3 cells displayed the canonical SASP phenomena. Current study suggested that senescent NIH-3T3 cells might be an appropriate in vitro SASP model of mouse cells.

A fluorescent turn-on probe for visualizing lysosomes in hypoxic tumor cells.

A fluorescent probe for fulfilling a lysosome targeting function in hypoxic tumor cells is reported, wherein azoreductase triggers a dramatic fluorescence enhancement and specific imaging of lysosomes in hypoxic cancer cells.

Synthesis and antidepressant activities of 4-(substituted-phenyl)tetrazolo[1,5-a]quinazolin-5(4H)-ones and their derivatives.

A series of novel 4-(substituted-phenyl) tetrazolo[1,5-a]quinazolin-5(4H)-ones (6a-x) and their derivatives with tetrazole and other heterocyclic substituents (7-14) were designed, synthesized, and evaluated for antidepressant activities in mice. Pharmacological tests showed that three compounds (6l, 6u, and 6v) at a dose of 50 mg/kg significantly reduced the immobility time in the forced swimming test. The most active compound was 4-(p-tolyl)tetrazolo[1,5-a]quinazolin-5(4H)-one (6v), which decreased the immobility time by 82.69 % at 50 mg/kg. Moreover, 6v did not affect spontaneous activity in the open-field test, and this effect was comparable to the antidepressant effect of fluoxetine. Noradrenaline (NE) and 5-hydroxytryptamine (5-HT) levels in the brains of mice in the test sample groups significantly increased at a dose of 50 mg/kg compared with that in the control group. The monoamine oxidase (MAO) level of all test groups was reduced, but this result was not significantly different between the groups. Therefore, we can infer that their underlying mechanisms may involve the regulation of brain monoamine neurotransmitter homeostasis, based on the detected content of NE, 5-HT, and MAO in mouse brain tissue.

Synthesis and Anticonvulsant Activity Evaluation of 4-Phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one and Its Derivatives.

A series of 4-(substituted-phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones (6a-x) with triazole and other heterocyclic substituents (7-14) were synthesized and the compounds were evaluated for their anticonvulsant activity and neurotoxicity by maximal electroshock (MES) and rotarod neurotoxicity tests. Among the compounds studied, 6o and 6q showed wide margins of safety with protective indices (PIs) that were much higher than those of currently used drugs (PI6o > 25.5, PI6q > 26.0). Compounds 6o and 6q showed significant oral activity against MES-induced seizures in mice, with ED50 values of 88.02 and 94.6 mg/kg, respectively. The two compounds were also found to have potent activity against seizures that were induced by pentylenetetrazole and bicuculline.

Synthesis of 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives and evaluation of their anticonvulsant activities.

This work concerns the design and synthesis of novel, substituted 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 5a-p prepared from 3-amino-2-thiophenecarboxylic acid methyl ester. The final compounds were screened for their in vivo anticonvulsant activity using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. Neurotoxicity (NT) was tested using a rotarod test. The structure-anticonvulsant activity relationship analysis revealed that the most effective structural motif involves a substituted phenol, especially when substituted with a single chlorine, fluorine or trifluoromethyl group (at the meta-position), or two chlorine atoms. These molecules possessed high activity according to the MES and scPTZ models. Quantitative assessment of the compounds after intraperitoneal administration in mice showed that the most active compound was 5-[3-(trifluoromethyl)phenoxy]thieno[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidine (5o) with ED50 values of 11.5 mg/kg (MES) and 58.9 mg/kg (scPTZ). Furthermore, compound 5o was more effective in the MES and scPTZ tests than the well-known anticonvulsant drugs carbamazepine and ethosuximide.