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GPR120, also called FFAR4, is preferentially expressed in the intestines, and can be stimulated by long-chain free fatty acids to increase the secretion of glucagon-like peptide-1 (GLP-1) from intestinal endocrine cells. It is known that GLP-1, as an incretin, can promote the insulin secretion from pancreatic cells in a glucose-dependent manner. Therefore, GPR120 is a potential drug target to treat type 2 diabetes. In this study, thiazolidinedione derivatives were found to be novel potent GPR120 agonists. Compound 5g, with excellent agonistic activity, selectivity, and metabolic stability, improved oral glucose tolerance in normal C57BL/6 mice in a dose-dependent manner. Moreover, compound 5g exhibited anti-diabetic activity by promoting insulin secretion in diet-induced obese mice. In summary, compound 5g might be a promising drug candidate for the treatment of type 2 diabetes.

Diabetes mellitus (DM) is a serious disease affecting human health. Numerous attempts have been made to develop safe and effective new antidiabetic drugs. Recently, a series of G protein-coupled receptors for free fatty acids (FFAs) have been described and characterized, and small molecule agonists and antagonists of these receptors show considerable promise for managing diabetes and related complications. FFA-activated GPR120 could stimulate the release of glucagon-like peptide-1(GLP-1), which can enhance the glucose-dependent secretion of insulin from pancreatic β cells. GPR120 is a promising target for treating type 2 DM (T2DM). Herein we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which was the first potent and selective GPR120 agonist. Among the designed compounds, 18 f showed excellent GPR120 activation activity and high selectivity for GPR40 in vitro. Compound 18 f dose-dependently improved glucose tolerance in normal mice, and no hypoglycemic side effects were observed at high dose. In addition, compound 18 f increased insulin release and displayed good antidiabetic effect in diet-induced obese mice. Molecular simulations illustrated that compound 18 f could enter the active site of GPR120 and interact with Arg99. Based on these observations, compound 18 f may be a promising lead compound for the design of novel GPR120 agonists to treat T2DM.

In this study, two series of 1,3,4-oxadiazole derivatives were designed and synthesized using the forced swimming test (FST) model to test the antidepressant activity of the target compound in vivo. Five compounds with potential activity were selected from the FST model to test affinity with 5-HT1A receptor in vitro. The results of the FST experiment showed that compound N-(3-((5-((4-chlorobenzyl)thio)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)acetamide (10g) showed the best antidepressant activity (DID = 58.93, percentage decrease in immobility duration in FST), similar to the activity of positive drug fluoxetine. Compound 10g also exhibited the most potent binding affinity to 5-HT1A receptors (Ki = 1.52 nM). The results of the in vivo 5-HT concentration estimation in mice showed that compound 10g may have an effect on the brain. The experimental results of exploratory activity in mice showed that compound 10g did not affect spontaneous activity in the open-field test model. Molecular docking was used to study the binding mode of compound 10g and the 5-HT1A receptor. Compound 10g showed significant interactions with residues at the active site on the 5-HT1A receptor. The physicochemical and pharmacokinetic properties of the target compounds were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.

Background Coumarin and 3,4-dihydroquinolinone nuclei are two heterocyclic rings that are important and widely exploited for the development of bioactive molecules. Here, we designed and synthesized a series of 3,4-dihydroquinolinone and coumarin derivatives (Compounds 8, 9, 11, 14, 15, 18-20, 23, 24 and 28 are new compounds) and studied their antidepressant activities. Methods Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mouse brain, by using ELISA. A 5-HT1A binding assay was also performed. The biological activities of the compounds were verified by molecular docking studies. The physicochemical and pharmacokinetic properties of the target compounds were predicted by Discovery Studio and ChemBioDraw Ultra. Results Of all the compounds tested, compound 7 showed the best antidepressant activity, which decreased the immobility time by 65.52 s in FST. However, in the open-field test, compound 7 did not affect spontaneous activity. The results of 5-HT concentration estimation in vivo showed that compound 7 may have an effect on the mouse brain. Molecular docking results indicated that compound 7 showed significant interactions with residues at the 5-HT1A receptor using homology modeling. The results show that compound 7 exhibits good affinity for the 5-HT1A receptor. Conclusion Coumarin and 3,4-dihydroquinolinone derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.

Background:Several series of pyrazole derivatives containing (thio) semicarbazide (4a-4h, 5a-5l, 6a-6f, 7a-7c) were designed and synthesized to screen dual inflammatory and antimicrobial activities.Methods:The products were characterized by1H NMR, 13C NMR and HRMS. In vitro LPS-induced TNF-α model and in vivo xylene-induced ear-edema model were used to evaluate their antiinflammatory activity. Their in vitro antimicrobial activities were evaluated using a serial dilution method against several gram-positive strains, gram-negative strains and a fungi strain.Results:Bioassays indicated that most of the compounds markedly inhibited the expression of TNF- α at the concentration of 20 µg/mL Compounds 5i, 6b, and 7b had comparable in vivo antiinflammatory activity to the reference drug dexamethasone at the dose of 50 mg/kg. In addition, several compounds showed antimicrobial activity against different strains, and compounds 5g and 5h exhibited potent inhibitory activities with the MIC value of 8 µg/mL against the Streptococcus pneumoniae CMCC 31968 and Staphylococcus aureus CMCC 25923, respectively. Compound 7b, which exhibited both anti-inflammatory and antimicrobial activities, should be studied as it is or after derivatization.Conclusion:It can be concluded that pyrazoles, with (thio)-semicarbazone moieties, have the potential to be developed into new anti-inflammatory agents.

In order to develop a novel herbicide containing the β-triketone motif, a series of 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one derivatives were designed and synthesized. The bioassay results showed that compound

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 1H NMR, 13C 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=104 m2) 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.

A series of aminoguanidine derivatives containing an acylhydrazone moiety was designed based on combination principles to find new antibacterial agents with wide spectra and high activities. The synthesized compounds were characterized by spectral methods and screened for their antibacterial activity. The results showed that several compounds provided great antimicrobial activities against Gram-positive bacteria (including the multidrug-resistant clinical isolates). Especially, this series of compounds presented high potency against

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.

The use of histamine H

Earthworms, as the first choice for soil monitoring and bio-remediation of cadmium (Cd)-contaminated soil, need to identify its mechanism under Cd stress. In this study, an artificial soil test method was used to determine the oxidative stress reaction indices, amino acid composition, and microbial community changes in earthworms under different stress durations and concentrations. For the first time, the canonical correlation analysis model and path analysis model were innovatively introduced into the data analysis to determine the mechanism that drives earthworm physiological functions after Cd stress. The results showed that in the low-stress concentration treatments (50–125 mg.kg−1 DW), there was a driving relationship between oxidative stress reaction and microbial community in earthworm, and the driving factor was glycyl-L-glutamic acid at 50 mg.kg−1 DW. With the increase of Cd stress intensity, the enzymes of oxidative stress promoted the survival microbes to begin to proliferate, and SOD became the main driving factor under 125 mg.kg−1 DW Cd stress. In the high-stress concentration treatments (250–500 mg.kg−1 DW), the driving effects were weakened or disappeared; while Cd-resistant microbial population appeared. This study provides a theoretical basis for the driving mechanism between oxidative stress effect and microbial community after Cd stress.

In this study, two series of 1,3,4-oxadiazole derivatives were designed and synthesized using the forced swimming test (FST) model to test the antidepressant activity of the target compound

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 (ED50) and 50% toxic dose (TD50). 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, ED50 = 8.9 mg/kg; scPTZ, ED50 = 10.2 mg/kg), which was greater than the activities of carbamazepine and ethosuximide. Compound 5b exhibited the most potent binding affinity toward the GABAA receptor (IC50 = 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 GABAA 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 GABAA receptor. Thus the present study has provided potential candidates for further investigation in epilepsy.

Naphthalimide platinum(IV) antitumor complexes with potential dual DNA damage mechanism were designed, synthesized and evaluated for antitumor activities. The incorporation of DNA targeted naphthalimide group to the platinum(IV) system exerts much positive impacts on their antitumor efficacy. The mechanism research reveals that the title compounds could interact with dsDNA in platinum(IV) form via the naphthalimide group and cause DNA lesion. The further reduction would release platinum(II) complexes and naphthalimide acids which would induce remarkable secondary damage to DNA. Furthermore, the naphthalimide platinum(IV) compounds could combine with human serum albumin via electrostatic force, which are favourable for their storage and transport in blood. Moreover, the title compounds exhibit higher accumulation in tumor cells, and exert lower toxic and higher safe properties than oxaliplatin in vivo.

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.

A series of 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine derivatives containing triazole and other heterocycle substituents (methyltriazole, tetrazole, and triazolone) is described. Two experimental methods, maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), were used to evaluate the anticonvulsant activity of the target compounds. Moreover, the neurotoxicity (NT) was tested using the Rotarod test. 5-(4-Chlorophenyl)-4,5-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6c) showed the best anticonvulsant activity. In the MES and PTZ experiments, the 50% effective dose (ED50 ) values of compound 6c were 9.5 and 20.5 mg/kg, respectively. From the therapeutic index (PI) values, 6c (MES and PTZ with PI values of 48.0 and 22.2, respectively) showed better safety than the clinical drugs carbamazepine (MES with PI value of 6.4) and ethosuximide (PTZ with PI value of 3.2). The biological activities of the compounds were verified by using molecular docking studies. Compound 6c showed significant interactions with residues at the benzodiazepine-binding site on gamma-aminobutyric acid A (GABAA ) receptors. The results of in vivo GABA estimation and bicuculline-induced seizures showed that 6c may have an effect on the GABA system. The physicochemical and pharmacokinetic properties of the target compounds were predicted.

The use of histamine H3 receptor (H3 R) antagonists is becoming a promising therapeutic approach for epilepsy. In this paper, a series of novel nonimidazole H3 R antagonists was synthesized and screened as antiepileptic drugs. All of these prepared antagonists displayed micromolar or submicromolar H3 R antagonistic activities in the cAMP response element luciferase screening assay. Compounds 5a (IC50 = 0.11 μM), 5b (IC50 = 0.56 μM), and 5f (IC50 = 0.78 μM) displayed the most potent H3 R antagonistic activities, with considerable potency when compared with pitolisant (IC50 = 0.51 μM). In the maximal electroshock (MES)-induced seizure model, compounds 5c, 5e, and 5g showed obvious protection for the electrostimulated mice, and the protection of 5g against the MES-induced seizures was fully abrogated when mice were cotreated with R-(α)-methyl-histamine, a central nervous system-penetrant H3 R agonist, suggesting that the potential therapeutic effect of 5g was observed to work through H3 R. These results indicate that the attempt to find a new antiepileptic drug among H3 R antagonists is practicable, but it is necessary to consider the log P of the molecules to ensure penetration of the blood-brain barrier.

In this study, a series of 3,4-dihydroquinolin-2(1H)-one derivatives were designed and synthesized using two experimental models, namely maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), to test the anticonvulsant activity of the target compound in vivo (i.p. in Kunming mice). The neurotoxicity (NT) of the target compound was measured by the rotating rod method (i.p. in Kunming mice). Six compounds with potential activity were selected from the two experimental models to test the 50% effective dose (ED50). In vitro binding experiments with the GABAA receptor were also performed. The results of the pharmacological experiments showed that compound 7-((5-(pentylthio)-1,3,4-oxadiazol-2-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (5b) showed the best anticonvulsant activity (MES, ED50 = 10.1 mg/kg; scPTZ, ED50 = 9.3 mg/kg), which was superior to activities shown by carbamazepine and ethosuximide, and it also exhibited the most potent binding affinity to GABAA receptors (IC50 = 0.12 μM). The GABA content in Wistar rat brains (i.p.) was also investigated, and the results showed that compound 5b may have a certain effect on the GABA system, as it increased the GABA concentration in the brain of rats. Molecular docking was used to study the binding mode of compound 5b and the GABAA receptor. Compound 5b showed significant interactions with residues at the benzodiazepines binding site on the GABAA receptor. The physicochemical and pharmacokinetic properties of the target compounds were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.0.

A novel series of benzoxazole derivatives containing 1,2,4-triazolone (5a-m) was designed. These compounds were synthesized in order to screen their anticonvulsant activities by the maximal electroshock seizure (MES) model and the subcutaneous pentylenetetrazole (sc-PTZ) seizure model in mice. The rotarod test was used to evaluate their neurotoxicities. Most of the compounds showed anti-MES activities at 100 and 300 mg/kg. Compound 5f, which showed potential anticonvulsant activity in the MES model with ED50 values of 22.0 mg/kg, was considered as the most promising one in this study. It exhibited greater safety than that of carbamazepine and valproate regarding neurotoxicity. The efficacy of compound 5f in inhibiting the tonic seizures and death induced by the convulsants 3-mercaptopropionic acid and BIC was also verified. In an enzyme-linked immunosorbent assay, compound 5f and the positive drug phenytoin significantly increased the γ-aminobutyric acid (GABA) level in the mouse brain. Further, pretreatment with an inhibitor of the GABA synthesizing enzyme dramatically raised the ED50 value of 5f in the MES model. These results confirmed that the compound 5f plays its anticonvulsive action via regulating the GABA function in the brain. Also, a docking study of the compound 5f in the benzodiazepine (BZD) binding site of the GABAA receptor confirmed possible binding of the compound 5f with BZD receptors.