In this study, a series of coumarin derivatives were designed and synthesized, their structures were characterized using nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) ...testing methods. In the pharmacological experiment, two behavior-monitoring methods, the forced swim test (FST) and the tail suspension test (TST), were used to determine the antidepressant activity of coumarin derivatives. Compounds that showed potential activity were analyzed for their effects on 5-hydroxytryptamine (5-HT) levels in the brains of mice. Molecular docking experiments to simulate the possible interaction of these compounds with the 5-HT1A receptor was also be predicted. The results of the pharmacological experiments showed that most coumarin derivatives exhibited significant antidepressant activity. Among these compounds, 7-(2-(4-(4-fluorobenzyl)piperazin-1-yl)-2-oxoethoxy)-2H-chromen-2-one (6i) showed the highest antidepressant activity. The results of the measurement of 5-HT levels in the brains of mice indicate that the antidepressant activity of coumarin derivatives may be mediated by elevated 5-HT levels. The results of molecular docking demonstrated that compound 6i had a significant interaction with amino acids around the active site of the 5-HT1A receptor in the homology model. The physicochemical and pharmacokinetic properties of the target compounds were also predicted using Discovery Studio (DS) 2020 and Chemdraw 14.0.
In this study, four series of piperazine derivatives were designed, synthesised and subjected to biological test, and compound 6a with potential antidepressant activity was obtained. An affinity ...assay of compound 6a with 5-hydroxytryptamine (serotonin, 5-HT)1A receptor (5-HT1AR) was undertaken, and the effects on the 5-HT level in the brains of mice were also tested. The results showed that compound 6a had the best affinity with 5-HT1AR (Ki = 1.28 nM) and significantly increased the 5-HT level. The expression levels of 5-HT1AR, BDNF, and PKA in the hippocampus were analysed by western blot and immunohistochemistry analyses. The results showed that the expression of 5-HT1AR, BDNF, and PKA in the model group was reduced compared to that of the control group, and compound 6a could reverse this phenomenon. Molecular docking was performed to investigate the interactions of the studied compound 6a with 5-HT1AR on the molecular level.
Epilepsy is a chronic neurological disorder that is more prevalent in children, and recurrent unprovoked seizures can lead to cognitive impairment. Numerous studies have reported the benefits of ...docosahexaenoic acid (DHA) on neurodevelopment and cognitive ability, while comparatively less attention has been given to eicosapentaenoic acid (EPA). Additionally, little is known about the effects and mechanisms of DHA and EPA in relation to seizure-induced cognitive impairment in the young rodent model. Current research indicates that ferroptosis is involved in epilepsy and cognitive deficiency in children. Further investigation is warranted to determine whether EPA or DHA can mitigate seizure-induced cognitive deficits by inhibiting ferroptosis. Therefore, this study was conducted to compare the effects of DHA and EPA on seizure-induced cognitive deficiency and reveal the underlying mechanisms focused on ferroptosis in a pentylenetetrazol (PTZ)-kindling young mice model. Mice were fed a diet containing DHA-enriched ethyl esters or EPA-enriched ethyl esters for 21 days at the age of 3 weeks and treated with PTZ (35 mg/kg, i.p.) every other day 10 times. The findings indicated that both EPA and DHA exhibited ameliorative effects on seizure-induced cognitive impairment, with EPA demonstrating a superior efficacy. Further mechanism study revealed that supplementation of DHA and EPA significantly increased cerebral DHA and EPA levels, balanced neurotransmitters, and inhibited ferroptosis by modulating iron homeostasis and reducing lipid peroxide accumulation in the hippocampus through activating the Nrf2/Sirt3 signal pathway. Notably, EPA exhibited better an advantage in ameliorating iron dyshomeostasis compared to DHA, owing to its stronger upregulation of Sirt3. These results indicate that DHA and EPA can efficaciously alleviate seizure-induced cognitive deficiency by inhibiting ferroptosis in PTZ-kindled young mice.
In this study, we synthetized a series of 5-aryl-4,5-dihydrotetrazolo1,5-
thieno2,3-
pyridine derivatives containing tetrazole and other heterocycle substituents, i.e., triazole, methyltriazole, and ...triazolone. The forced swim test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The compound 5-4-(trifluoromethyl)phenyl-4,5-dihydrotetrazolo1,5-
thieno2,3-
pyridine (
) showed the highest antidepressant activity, with a reduced immobility time of 55.33% when compared with the control group. Using an open-field test, compound
was shown to not affect spontaneous activity of mice. The determination of in vivo 5-hydroxytryptamine (5-HT) concentration showed that compound
may have an effect in the mouse brain. The biological activities of all synthetized compounds were verified by molecular docking studies. Compound
showed significant interactions with residues of the 5-HT
receptor homology model.
GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an ...incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound 11b showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, 11b showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound 11b could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound 11b might be a promising drug candidate for the treatment of T2DM.
Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. ...Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated researchers to explore novel antidiabetic agents with different mechanisms of action. G-protein Coupled Receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), which is activated by medium-chain and long-chain fatty acids, has emerged as an interesting potential target for the treatment of metabolic disorders. Herein, we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which is susceptible to
-oxidation and loses its GPR120 agonistic activity in vivo. Among the designed compounds,
showed excellent agonistic activity and selectivity and could improve glucose tolerance in normal mice in a dose-dependent manner. In addition, the compound
displayed good antidiabetic effects in diet-induced obese (DIO) mice and elevated insulin levels. Molecular simulations illustrated that compound
could enter the active site of GPR120 and interact with ARG99, which plays an important role in GPR120 activation. Based on these observations, compound
may be a promising lead compound deserving of further biological evaluation and structural modifications.
Soil cadmium (Cd) pollution has received increasing attention from scholars. In the field of Cd pollution remediation, there is an urgent need to study the combined bioremediation technology of ...earthworms and microbes. In this paper, a short-term stress test and a long-term stress test were conducted.
Eisenia fetida
were inoculated into artificial soil that was contaminated with Cd. After different Cd stress times, the regulation process between the microbial communities in the earthworms and in the soil was studied. Canonical correlation analysis and the TOPSIS method were combined to establish a mathematical model for data analysis, and the changes in the carbon source utilization intensity by microbes were analysed. The results showed that in the short-term stress tests, the regulation process could be divided into five stages. Specifically, after 1–3 days of stress, the microbial community in the earthworms regulated the soil microbial community, but on the 3rd day, the regulation was weakened. On the 4th day, the soil microbial community was affected not only by the microbes in the earthworms but also by the increasing intensity of Cd stress. After 5 days of stress, the microbial communities in the earthworms and the soil were both greatly affected by Cd poisoning, and the microbes transitioned from stable to declining. At 6–7 days, the microbes in the earthworms gained control over those in the soil once again, and the Cd-tolerant microbes began to appear and proliferate. At 8–10 days, the regulation of the soil microbes by the earthworm microbes weakened, while the Cd-tolerant population in the soil microbial communities gradually evolved at this stage to adapt to the increasing Cd stress. The long-term stress tests showed that the difference between the microbial communities in the soil and in the earthworms increased, and there was almost no regulation between them.
In order to develop a novel herbicide containing the 2,1-benzothiazine motif, a series of 3-acetyl-4-hydroxy-2,1-benzothiazine derivatives was synthesized. All the target compounds were confirmed by
...1
H NMR,
13
C NMR, and high-resolution mass spectrometry(HRMS). In addition, the crystal structure of compound T27 was determined by single crystal X-ray diffraction. The bioassay results showed that some of the 3-acetyl-4-hydroxy-2,1-benzothiazine derivatives(T13, T15, T22, and T24) showed good herbicidal activity at a dosage of 100 μg/mL. Among them, compounds T22 and T24 showed promising post-emergent herbicidal activities against
Brassica campestris
and
Amaranthus retroflexus
even at a dosage of 375 g/ha(1 ha=10
4
m
2
) in the greenhouse test. Studies on the structure-activity relationship demonstrated that the type of acetyl group played an important role in the herbicidal activity, and that the introduction of a phenoxyacetyl group at the 3-position of 2,1-benzothiazine was beneficial in improving the herbicidal activity. The present study also indicated that 3-phenoxyacetyl-4-hydroxy-2,1-benzothiazine could be a potential lead compound for further development of novel 2,1-benzothiazine-containing herbicides.
In this study, a series of 1,3,4-oxadiazole derivatives (5a-s, 10a-s, and 16a-d) were designed and synthesized using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) models, to ...test the anticonvulsant activity of the target compounds in vivo. The neurotoxicity (NT) of the target compounds was measured using the rotating rod (ROT) method. Seven compounds with potential activity were selected to test the 50% effective dose (ED
) and 50% toxic dose (TD
). Pharmacological experiments revealed that 6-((5-(pentylthio)-1,3,4-oxadiazol-2-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (5b) showed the best anticonvulsant activity (MES, ED
= 8.9 mg/kg; scPTZ, ED
= 10.2 mg/kg), which was greater than the activities of carbamazepine and ethosuximide. Compound 5b exhibited the most potent binding affinity toward the GABA
receptor (IC
= 0.11 μM) in the in vitro binding experiments. Compound 5b displayed significant anxiolytic activity at a low dose (1 mg/kg) in the elevated plus maze (EPM) test. The GABA content in rat brains was also investigated, and the results showed that compound 5b might have affected the GABA system. In our molecular docking experiment, compound 5b showed significant interactions with residues present at the benzodiazepine binding site on the GABA
receptor. The structure and physicochemical and pharmacokinetic properties of the target compound were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.0. Finally we demonstrated that compound 5b mainly acted on GABA
receptor. Thus the present study has provided potential candidates for further investigation in epilepsy.
α-succinimide-substituted allenoates were employed as phosphine acceptors in phosphine-catalyzed (4 + 2) annulation with 1,1-dicyanoalkenes. They served as C4 synthons in the annulation reaction ...under mild reaction conditions and produced hexahydroisoindole derivatives in moderate to high yields with good to excellent diastereoselectivities.
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