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.
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-HT1A receptor homology model.
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.
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