{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:46:39Z","timestamp":1788266799240,"version":"build-2803163510"},"reference-count":30,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T00:00:00Z","timestamp":1771718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Propofol is used worldwide as a short-acting intravenous anesthetic in clinical practice; however, side effects such as injection pain and respiratory depression remain clinically relevant. Therefore, identification of safer propofol analogs is required. Method: In response to the urgent need for optimized potency and reduced side effects, a series of dihydrobenzofuran derivatives were designed as expectedly better propofol analogs through conformational restriction. A loss of righting reflex assay was conducted to evaluate the sedative\/anesthetic properties of the synthesized compounds, and a respiratory depression test was performed for safety assessment. Results: Most of the designed compounds were shown to possess promising anesthetic properties as propofol analogs. The represented 53A had higher potency and a wider safety margin (ED50:3.898 vs. 8.040 mg\/kg in mice; 2.985 vs. 5.894 mg\/kg in rats; TI (therapeutic index): 6.172 vs. 5.061 in mice; 4.362 vs. 2.580 in rats) than propofol, and fast onset and recovery times were maintained. The phosphate prodrug 56A also exhibited better efficiency and safety than fospropofol, along with a longer duration and faster recovery time in sedative profiles. Furthermore, alleviation of the adverse effects of respiratory depression has been demonstrated. Conclusions: 53A has the potential to be selected as a preclinical candidate for clinical development.<\/jats:p>","DOI":"10.3390\/ph19020342","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T10:00:52Z","timestamp":1771840852000},"page":"342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel Propofol Analogs: Design, Synthesis and Evaluation of Dihydrobenzofuran Derivatives as General Anesthetics"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0710-2865","authenticated-orcid":false,"given":"Jun-Jie","family":"Shi","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing 210093, China"},{"name":"Jiangsu Engineering Research Center for Neurological Drugs, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221007, China"},{"name":"Shanghai Shujing Biopharma Co., Ltd., Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Quan","family":"Feng","sequence":"additional","affiliation":[{"name":"Jiangsu Engineering Research Center for Neurological Drugs, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221007, China"},{"name":"Shanghai Shujing Biopharma Co., Ltd., Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Hai","family":"Zou","sequence":"additional","affiliation":[{"name":"Shanghai Shujing Biopharma Co., Ltd., Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Huo","sequence":"additional","affiliation":[{"name":"Shanghai Shujing Biopharma Co., Ltd., Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Han","family":"Ma","sequence":"additional","affiliation":[{"name":"Shanghai Shujing Biopharma Co., Ltd., Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Jing","family":"He","sequence":"additional","affiliation":[{"name":"Jiangsu Engineering Research Center for Neurological Drugs, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Hong","family":"Wan","sequence":"additional","affiliation":[{"name":"Jiangsu Engineering Research Center for Neurological Drugs, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221007, China"},{"name":"Shanghai Shujing Biopharma Co., Ltd., Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Qing","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Engineering Research Center for Neurological Drugs, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Jing","family":"Hu","sequence":"additional","affiliation":[{"name":"Jiangsu Engineering Research Center for Neurological Drugs, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221007, China"},{"name":"Shanghai Shujing Biopharma Co., Ltd., Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Long","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing 210093, China"},{"name":"Jiangsu Engineering Center of Biointelligent Materials, Medical School, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Hui","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Engineering Research Center for Neurological Drugs, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1021\/jm00186a013","article-title":"Synthesis, biological evaluation, and preliminary structure-activity considerations of a series of alkylphenols as intravenous anesthetic agents","volume":"23","author":"James","year":"1980","journal-title":"J. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/978-3-540-74806-9_11","article-title":"Propofol","volume":"182","author":"Vanlersberghe","year":"2008","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/367607a0","article-title":"Molecular and cellular mechanisms of general anaesthesia","volume":"367","author":"Franks","year":"1994","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1097\/00000542-199304000-00020","article-title":"The role of the GABAA receptor chloride channel complex in anesthesia","volume":"78","author":"Tanelian","year":"1993","journal-title":"Anesthesiology"},{"key":"ref_5","first-page":"472","article-title":"Reducing pain during propofol injection: The role of the solvent","volume":"82","author":"Doenicke","year":"1996","journal-title":"Anesth. Analg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1213\/00000539-199712000-00040","article-title":"Pharmacokinetics and pharmacodynamics of propofol in a new solvent","volume":"85","author":"Doenicke","year":"1997","journal-title":"Anesth. Analg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3210","DOI":"10.1021\/jm010461a","article-title":"4D-QSAR analysis of a set of propofol analogues: Mapping binding sites for an anesthetic phenol on the GABAA receptor","volume":"45","author":"Krasowski","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/S0022-3565(24)29544-6","article-title":"General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of \u03b3-Aminobutyric Acid (GABA) current at the GABAA receptor but not with lipid solubility","volume":"297","author":"Krasowski","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1093\/bja\/aeq190","article-title":"New drugs and technologies, intravenous anaesthesia is on the move (again)","volume":"105","author":"Sneyd","year":"2010","journal-title":"Br. J. Anaesth."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3606","DOI":"10.1021\/acs.jmedchem.7b00254","article-title":"Design, synthesis, and evaluation of novel 2,6-disubstituted phenol derivatives as general anesthetics","volume":"60","author":"Qin","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S0960-894X(01)00088-9","article-title":"Watersoluble propofol analogues with intravenous anaesthetic activity","volume":"11","author":"Cooke","year":"2001","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1016\/S0960-894X(03)00346-9","article-title":"Novel water soluble 2,6-dimethoxyphenyl ester derivatives with intravenous anaesthetic activity","volume":"13","author":"Bennett","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1097\/MJT.0b013e318256ecfc","article-title":"A double-blind, randomized, multicenter, dose-ranging study to evaluate the safety and efficacy of fospropofol disodium as an intravenous sedative for colonoscopy in high-risk populations","volume":"20","author":"Bergese","year":"2013","journal-title":"Am. J. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1016\/j.bmcl.2013.01.034","article-title":"Synthesis and characterization of novel quick release propofol prodrug via lactonization","volume":"23","author":"Yang","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1093\/bja\/aet218","article-title":"Efficacy comparison of the novel water-soluble propofol prodrug HX0969w and fospropofol in mice and rats","volume":"111","author":"Zhou","year":"2013","journal-title":"Br. J. Anaesth."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejps.2018.09.024","article-title":"An improved water-soluble prodrug of propofol with high molecular utilization and rapid onset of action","volume":"127","author":"Zhang","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7857","DOI":"10.1021\/acs.jmedchem.0c00698","article-title":"Design, synthesis and activity study of a water-soluble, rapid-release propofol prodrug","volume":"63","author":"Liu","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27510","DOI":"10.1039\/C9RA04917G","article-title":"Natural source, bioactivity and synthesis of benzofuran derivatives","volume":"9","author":"Miao","year":"2019","journal-title":"RSC Adv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"137098","DOI":"10.1016\/j.molstruc.2023.137098","article-title":"Furan and benzofuran derivatives as privileged scaffolds as anticancer agents: SAR and docking studies (2010 to till date)","volume":"1299","author":"Patel","year":"2023","journal-title":"J. Mol. Struct."},{"key":"ref_20","unstructured":"Feng, J., Zou, Y., and Wan, Z. (2023). Benzo-Ring-Containing Derivative, and Preparation Method Thereof and Use Thereof. (WO Patent Application 2023\/011634 A1)."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1002\/jhet.5570250350","article-title":"Benzofurans. Ketone intermediates in the Perkin reaction","volume":"25","author":"Brady","year":"1988","journal-title":"J. Heterocyclic Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1097\/00000542-200106000-00020","article-title":"Anesthetic properties of 4-iodopropofol: Implications for mechanism of anesthesia","volume":"94","author":"Lingamaneni","year":"2001","journal-title":"Anesthesiology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41586-020-2654-5","article-title":"Shared structural mechanisms of general anaesthetics and benzodiazepines","volume":"585","author":"Kim","year":"2020","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1002\/cmdc.202000461","article-title":"Synthesis and pharmacological evaluation of \u03c32 receptor ligands based on a 3-alkoxyisoxazole scaffold: Potential antitumor effects against osteosarcoma","volume":"16","author":"Shi","year":"2021","journal-title":"ChemMedChem"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1007\/s00540-019-02676-8","article-title":"Lipid emulsion, but not propofol, induces skeletal muscle damage and lipid peroxidation","volume":"33","author":"Chaki","year":"2019","journal-title":"J. Anesth."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kazi, M., Alqahtani, A., Alharbi, M., Ahmad, A., Hussain, M.D., Alothaid, H., and Aldughaim, M.S. (2023). The development and optimization of lipid-based self-nanoemulsifying drug delivery systems for the intravenous delivery of propofol. Molecules, 28.","DOI":"10.3390\/molecules28031492"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chu, Y., Sun, T., Xie, Z., Sun, K., and Jiang, C. (2022). Physicochemical characterization and pharmacological evaluation of novel propofol micelles with low-lipid and low-free propofol. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14020414"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Do\u011fanay, F., Ak, R., Al\u0131\u015fkan, H., Abut, S., S\u00fcmer, E., and Onur, \u00d6. (2019). The effects of intravenous lipid emulsion therapy in the prevention of depressive effects of propofol on cardiovascular and respiratory systems: An experimental animal study. Medicina, 55.","DOI":"10.20944\/preprints201808.0136.v2"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wu, C., Zhang, W., Liu, J., Zhang, W., and Ke, B. (2021). Efficacy and safety of Fospropofol disodium for injection in general anesthesia induction for adult patients: A phase 3 trial. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.687894"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhao, Z., Jin, X., Li, Y., Wang, X., Cui, Y., Zhang, B., Kang, Y., Zhang, G., Chu, Q., and Zhang, J. (2024). Efficacy and safety of Fospropofol disodium sedation for same-day bidirectional endoscopy in elderly patients: Protocol for a prospective, single-center, randomized, double-blind, non-inferiority trial. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1378081"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/2\/342\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T09:11:43Z","timestamp":1771924303000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/2\/342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,22]]},"references-count":30,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ph19020342"],"URL":"https:\/\/doi.org\/10.3390\/ph19020342","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,22]]}}}