{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T08:08:27Z","timestamp":1779178107346,"version":"3.51.4"},"reference-count":65,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Science","award":["2022-I2M-1-018"],"award-info":[{"award-number":["2022-I2M-1-018"]}]},{"name":"CAMS Innovation Fund for Medical Science","award":["2022-I2M-2-001"],"award-info":[{"award-number":["2022-I2M-2-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pterostilbene (Pts), a small molecule stilbenoid and a dimethyl analogue of the star molecule resveratrol, exerts significant blood\u2013brain barrier protection on cerebral ischemia-reperfusion injury and has received extensive attention. This study performed structural optimizations on Pts to obtain a series of derivatives and investigated their anti-ischemic activities both in vitro and in vivo, aiming to identify candidates with high safety and improved efficacy compared with Pts. The ADMET method was used to predict the drug-likeness of a series of Pts derivatives, and in vitro MTT cell viability analysis was conducted on neuroblastoma cells (SH-SY5Y) and brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation\/reperfusion (OGD\/R) injury. On the basis of the cytotoxicity results, four derivatives (NO. 1, NO. 3, NO. 5, and NO. 7) were selected for subsequent in vitro and in vivo biological activities evaluation. These compounds exhibited significantly higher TI values (18.29\u201330.61) in OGD\/R-injured hBMECs compared with Pts (7.63) and effectively suppressed apoptosis, promoted cell migration, and enhanced tube formation capacity. In vivo, NO. 3 (5 mg\/kg, ip., 7 d) demonstrated superior efficacy compared to Pts in improving cerebral blood flow, reducing infarction volume, enhancing neurological function, and modulating serum biomarker levels in middle cerebral artery occlusion\/reperfusion (MCAO\/R) rats, whereas NO. 1 and NO. 7 showed comparable efficacy to Pts. The acute intraperitoneal toxicity of NO. 3 was conducted and showed that the LD50 of NO. 3 was estimated to be more than 300 mg\/kg. In this study, the rational design and comprehensive evaluation of Pts derivatives were reported. Compound NO. 3 demonstrated superior pharmacological efficacy to Pts both in vitro and in vivo, and it may be a promising therapeutic candidate for ischemic stroke intervention.<\/jats:p>","DOI":"10.3390\/ijms27104512","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:35:43Z","timestamp":1779176143000},"page":"4512","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural Optimization of Pterostilbene, a Promising Lead Molecule, and Evaluation of Its Derivatives via ADMET Prediction and In Vitro\/In Vivo Anti-Cerebral Ischemic Activity"],"prefix":"10.3390","volume":"27","author":[{"given":"Kecan","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China"},{"name":"National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaxin","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China"},{"name":"National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanan","family":"Dai","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China"},{"name":"National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4286-6665","authenticated-orcid":false,"given":"Zhihong","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China"},{"name":"National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","unstructured":"GBD 2016 Stroke Collaborators (2019). 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