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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-HT 1A R) 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-HT 1A R ( K i = 1.28 nM) and significantly increased the 5-HT level. The expression levels of 5-HT 1A R, BDNF, and PKA in the hippocampus were analysed by western blot and immunohistochemistry analyses. The results showed that the expression of 5-HT 1A R, 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-HT 1A R on the molecular level.

The use of histamine H 3 receptor (H 3 R) antagonists is becoming a promising therapeutic approach for epilepsy. In this paper, a series of novel nonimidazole H 3 R antagonists was synthesized and screened as antiepileptic drugs. All of these prepared antagonists displayed micromolar or submicromolar H 3 R antagonistic activities in the cAMP response element luciferase screening assay. Compounds 5a (IC 50  = 0.11 μM), 5b (IC 50  = 0.56 μM), and 5f (IC 50  = 0.78 μM) displayed the most potent H 3 R antagonistic activities, with considerable potency when compared with pitolisant (IC 50  = 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 H 3 R agonist, suggesting that the potential therapeutic effect of 5g was observed to work through H 3 R. These results indicate that the attempt to find a new antiepileptic drug among H 3 R antagonists is practicable, but it is necessary to consider the log P of the molecules to ensure penetration of the blood-brain barrier., (© 2020 Deutsche Pharmazeutische Gesellschaft.)

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 Staphylococcus aureus , among which the derivative 3f was the most promising one with a MIC value of 4 μg/mL. Compound 3d, with a tertiary butyl group, was found to have the broad spectrum inhibitory capacity, which is effective to eight strains and showed the most potent inhibitory activity against B. subtilis CMCC 63501 with a MIC value of 4 μg/mL. What's more, compound 3d also presented high activities against four multidrug-resistant strains, which were comparable or potent to oxacillin and penicillin. Molecular docking studies revealed that H-bond interaction with amino acid residue THR81 and alkyl hydrophobic interaction with residue ALA246 of FabH were crucial for their binding force and in-vitro antimicrobial activities.

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 (ED 50 ). In vitro binding experiments with the GABA A 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, ED 50  = 10.1 mg/kg; scPTZ, ED 50  = 9.3 mg/kg), which was superior to activities shown by carbamazepine and ethosuximide, and it also exhibited the most potent binding affinity to GABA A receptors (IC 50  = 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 GABA A receptor. Compound 5b showed significant interactions with residues at the benzodiazepines binding site on the GABA A receptor. The physicochemical and pharmacokinetic properties of the target compounds were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.0., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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-HT 1A 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-HT 1A receptors ( K i = 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-HT 1A receptor. Compound 10g showed significant interactions with residues at the active site on the 5-HT 1A receptor. The physicochemical and pharmacokinetic properties of the target compounds were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

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 (ED 50 ) 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 (GABA A ) 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., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

In this study, we synthetized a series of 5-aryl-4,5-dihydrotetrazolo[1,5- a ]thieno[2,3- e ]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-dihydrotetrazolo[1,5- a ]thieno[2,3- e ]pyridine ( 4i ) 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 4i was shown to not affect spontaneous activity of mice. The determination of in vivo 5-hydroxytryptamine (5-HT) concentration showed that compound 4i may have an effect in the mouse brain. The biological activities of all synthetized compounds were verified by molecular docking studies. Compound 4i showed significant interactions with residues of the 5-HT 1A receptor homology model.