{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T01:12:50Z","timestamp":1783127570763,"version":"3.54.6"},"reference-count":43,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Shandong","award":["ZR2022MB064"],"award-info":[{"award-number":["ZR2022MB064"]}]},{"name":"Natural Science Foundation of Shandong","award":["LCUGYTD2022-04"],"award-info":[{"award-number":["LCUGYTD2022-04"]}]},{"name":"\u201cGuangyue Young Scholar Innovation Team\u201d of Liaocheng University","award":["ZR2022MB064"],"award-info":[{"award-number":["ZR2022MB064"]}]},{"name":"\u201cGuangyue Young Scholar Innovation Team\u201d of Liaocheng University","award":["LCUGYTD2022-04"],"award-info":[{"award-number":["LCUGYTD2022-04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>To discover novel, potent anticonvulsant compounds, a series of compounds containing triazole structural fragments were synthesized and evaluated for their anticonvulsant activity. Compounds 6f (maximal electroshock (MES), 50% effective dose (ED50) = 13.1 mg\/kg; subcutaneous pentylenetetrazole (scPTZ), ED50 = 19.7 mg\/kg) and 6l (MES, ED50 = 9.1 mg\/kg; scPTZ, ED50 = 19.0 mg\/kg) showed the best activity in MES and scPTZ tests. The results of an affinity test showed that the potent compounds had better binding to the GABAA receptors. The results of an inhibitory neurotransmitter GABA content test in brain tissue indicated that compounds 6f and 6l exerted anticonvulsant activity which may be associated with the increase of GABA content in the rat brain. Elevated plus maze (EPM) assay results showed that compounds 6f and 6l possessed anxiolytic effects, and their effects correlated with the binding sites of benzodiazepines (BZs) in the GABAA receptors. Molecular docking was performed to investigate the interactions of the studied compound 6l with the GABAA receptors on the molecular level.<\/jats:p>","DOI":"10.3390\/molecules30163400","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T13:28:22Z","timestamp":1755523702000},"page":"3400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design, Synthesis, and Pharmacological Activity of the N-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-substituted-amide Derivatives"],"prefix":"10.3390","volume":"30","author":[{"given":"Lina","family":"Hu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large-Scale Preparation, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjiao","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large-Scale Preparation, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medicine, Foshan University, Foshan 528000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9843-0601","authenticated-orcid":false,"given":"Hui","family":"Yan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large-Scale Preparation, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuekun","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large-Scale Preparation, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8435-8135","authenticated-orcid":false,"given":"Shiben","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large-Scale Preparation, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s13577-021-00624-x","article-title":"Liquid biopsies in epilepsy: Biomarkers for etiology, diagnosis, prognosis, and therapeutics","volume":"35","author":"Whitlock","year":"2022","journal-title":"Hum. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109833","DOI":"10.1016\/j.yebeh.2024.109833","article-title":"Post-traumatic stress-disorder in epilepsy: Meta-analysis of current evidence","volume":"157","author":"Pepi","year":"2024","journal-title":"Epilepsy Behav."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/S1474-4422(20)30220-9","article-title":"Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: A retrospective multicentre cohort study","volume":"19","author":"Lamberink","year":"2020","journal-title":"Lancet Neural."},{"key":"ref_4","first-page":"185","article-title":"Emerging personalized virtual brain models: Next-generation resection neurosurgery for durg-resistant epilepsy?","volume":"6","author":"Wang","year":"2023","journal-title":"Acta Epileptol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1111\/j.1528-1167.2009.02397.x","article-title":"Definition of drug resistant epilepsy: Consensus Proposal by the ad hoc Task Force of the ILAE commission on Therapeutic strategies","volume":"51","author":"Kwan","year":"2010","journal-title":"Epilepsia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1001\/archneur.58.10.1543","article-title":"The early identification of candidotes for epilepsy surgery","volume":"58","author":"Dlugos","year":"2001","journal-title":"Arch. Neurol."},{"key":"ref_7","unstructured":"Zahrani, N.A.A. (2025). Design and Synthesis of Heptadecane-Linked 1,2,4-Triazoles As Antimicrobial Agents. Chem. Biodivers."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hong, S., Lu, H.Z., Tian, D.W., Chang, Y., Lu, Q., and Gao, F. (2025). Discovery of triazole derivatives for biofilm disruption, anti-inflammation and metal ion chelation. Front. Chem., 13.","DOI":"10.3389\/fchem.2025.1545259"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mahmoud, E., Abdelhamid, D., Mohammed, A.F., Almarhoon, Z.M., Br\u00e4se, S., Youssif, B.G.M., Hayallah, A.M., and Abdel-Aziz, M. (2025). Design, Synthesis, and Antiproliferative Activity of Novel Indole\/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors. Pharmaceuticals, 18.","DOI":"10.3390\/ph18020275"},{"key":"ref_10","first-page":"1","article-title":"3-(1H-pyrazole-1-yl\/1H-1,2,4-triazole-1-yl)-N-propananilide Derivatives: Design, Synthesis and Neuroprotectivity Potential Against 6-OHDA Induced Neurotoxicity Model","volume":"22","author":"Saylam","year":"2025","journal-title":"Turk. J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1021\/acsomega.4c07896","article-title":"Next-Generation Carbazole-Linked 1,2,4-Triazole-Thione Derivatives: Strategic Design, Synthesis, Molecular Docking, and Evaluation of Antidiabetic Potential","volume":"10","author":"Capan","year":"2024","journal-title":"ACS Omega"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117340","DOI":"10.1016\/j.ejmech.2025.117340","article-title":"Optimization of pyrazole\/1,2,4-triazole as dual EGFR\/COX-2 inhibitors: Design, synthesis, anticancer potential, apoptosis induction and cell cycle analysis","volume":"287","author":"Kahk","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Paruch, K., Kapro\u0144, B., \u0141uszczki, J.J., Paneth, A., and Plech, T. (2023). Effect of Linker Elongation on the VGSC Affinity and Anticonvulsant Activity among 4-Alkyl-5-aryl-1,2,4-triazole-3-thione Derivatives. Molecules, 28.","DOI":"10.3390\/molecules28135287"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"141611","DOI":"10.1016\/j.molstruc.2025.141611","article-title":"Design, synthesis and pharmacological evaluation of triazolopyrimidines derivatives as novel agonists for benzodiazepine receptor","volume":"1331","author":"Li","year":"2025","journal-title":"J. Mol. Struct."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"112672","DOI":"10.1016\/j.ejmech.2020.112672","article-title":"Synthesis of 1,3,4-oxadiazole derivatives with anticonvulsant activity and their binding to the GABAA receptor","volume":"206","author":"Wang","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Valipour, M., Ghasemian, M., Karima, S., Khatir, Z.Z., Aghamiri, H., Shaki, F., Akbari, S., Amiri, F.T., Hosseini, A., and Jafari-Sabet, M. (2025). Design, synthesis, and structure-activity relationships of five-membered heterocyclic incorporated aryl(alkyl)azoles: From antiproliferative thiazoles to safer anticonvulsant oxadiazoles. Bioorg. Chem., 155.","DOI":"10.1016\/j.bioorg.2024.108117"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"32922","DOI":"10.1039\/D4RA06121G","article-title":"New triazole-based hybrids as neurotropic agents","volume":"14","author":"Sirakanyan","year":"2024","journal-title":"RSC Adv."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Jahani, R., Reza Abtahi, S., Nematpour, M., Fasihi Dastjerdi, H., Chamanara, M., Hami, Z., and Paknejad, B. (2020). Design, synthesis, and pharmacological evaluation of novel 1,2,4-triazol-3-amine derivatives as potential agonists of GABA(A) subtype receptors with anticonvulsant and hypnotic effects. Bioorg. Chem., 104.","DOI":"10.1016\/j.bioorg.2020.104212"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e202400337","DOI":"10.1002\/ajoc.202400337","article-title":"Novel Metal-Free Porphyrin with Ionic Liquid and Sulphonic Acid Moieties for Visible Light Assisted Photocatalytic CN Coupling of Heterocyclic Compounds with Aryl Halides","volume":"13","author":"Yadav","year":"2024","journal-title":"Asian J. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.jmgm.2008.12.004","article-title":"Molecular modeling of ligand-receptor interactions in GABAc receptor","volume":"27","author":"Osolodkin","year":"2009","journal-title":"J. Mol. Graph. Model."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1007\/s11224-022-02029-4","article-title":"Investigation of [3H]diazepam derivatives as allosteric modulators of GABAA receptor \u03b11\u03b22\u03b32 subtypes: Combination of molecular docking\/dynamic simulations, pharmacokinetics\/druglikeness prediction, and QSAR analysis","volume":"34","author":"Djebaili","year":"2023","journal-title":"Struct. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.mencom.2023.06.034","article-title":"A novel urea derivative anticonvulsant: In vivo biological evaluation, radioreceptor analysis of GABAA receptors and molecular docking studies of enantiomers","volume":"33","author":"Shushpanova","year":"2023","journal-title":"Mendeleev. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4582","DOI":"10.1038\/s41467-022-32212-4","article-title":"Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities","volume":"13","author":"Zhu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Golani, L.K., Mian, M.Y., Ahmed, T., Pandey, K.P., Mondal, P., Sharmin, D., Rezvanian, S., Witkin, J.M., and Cook, J.M. (2022). Rationalizing the binding and \u03b1 subtype selectivity of synthesized imidazodiazepines and benzodiazepines at GABAA receptors by using molecular docking studies. Bioorg. Med. Chem., 62.","DOI":"10.1016\/j.bmcl.2022.128637"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"301","DOI":"10.17807\/orbital.v13i4.1607","article-title":"Combined conceptual-DFT, quantitative MEP analysis, and molecular docking study of benzodiazepine analogs","volume":"13","author":"Djebaili","year":"2021","journal-title":"Orbital Electron. J. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/j.1528-1157.1978.tb04507.x","article-title":"Antiepileptic drug development: II. Anticonvulsant drug screening","volume":"19","author":"Krall","year":"1978","journal-title":"Epilepsia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3949\/ccjm.51.2.293","article-title":"Antiepileptic drug development program","volume":"51","author":"Poter","year":"1984","journal-title":"Cleve. Clin. Q."},{"key":"ref_28","unstructured":"Levy, R.H., Mattson, R.H., and Meldrum, B.S. (1995). General principles: Experimental selection, quantiffcation and evaluation of antiepileptic drugs. Antiepileptic Drugs, Raven Press. [4th ed.]."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1523\/JNEUROSCI.4639-11.2012","article-title":"Dihydromyricetin as a novel anti-alcohol intoxication medication","volume":"32","author":"Shen","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_30","first-page":"101","article-title":"Thin-layer chromatographic method for estimation of gamma-aminobutyric acid from brain","volume":"23","author":"Gokani","year":"1979","journal-title":"Indian J. Physiol. Pharmacol."},{"key":"ref_31","first-page":"376","article-title":"A convenient method for determining serum and bile phosphatase activity","volume":"31","author":"King","year":"1934","journal-title":"Can. Med. Assoc. J."},{"key":"ref_32","unstructured":"Rodgers, R., Cole, J., Cooper, S., and Hendrie, C. (1994). Ethology and Psychopharmacology, John Wiley and Sons Ltd."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.euroneuro.2010.02.007","article-title":"Previous stress exposure enhances both anxietylike behaviour and p35 levels in the basolateral amygdala complex: Modulation by midazolam","volume":"20","author":"Bignante","year":"2010","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"6","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-319-15976-8_1","article-title":"Tackling exascale software challenges in molecular dynamics simulations with GROMACS","volume":"8759","author":"Abraham","year":"2015","journal-title":"Solving Softw. Chall. Exascale"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1093\/bioinformatics\/btt055","article-title":"GROMACS 4.5: A high-throughput and highly parallel open source molecular simulation toolkit","volume":"29","author":"Pronk","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/ct700301q","article-title":"GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation","volume":"4","author":"Hess","year":"2008","journal-title":"J. Chem. Theory. Comput."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3586","DOI":"10.1021\/jp973084f","article-title":"All-atom empirical potential for molecular modeling and dynamics studies of proteins","volume":"102","author":"MacKerell","year":"1998","journal-title":"J. Phys. Chem. B."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","article-title":"LINCS: A linear constraint solver for molecular simulations","volume":"18","author":"Hess","year":"1997","journal-title":"J. Comput. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"014101","DOI":"10.1063\/1.2408420","article-title":"Canonical sampling through velocity rescaling","volume":"126","author":"Bussi","year":"2007","journal-title":"J. Phys. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular Dynamics with Coupling to an External Bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Phys. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/16\/3400\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:29:39Z","timestamp":1760034579000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/16\/3400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,18]]},"references-count":43,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["molecules30163400"],"URL":"https:\/\/doi.org\/10.3390\/molecules30163400","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,18]]}}}