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PDE4 is a key regulator of cAMP signaling and a clinically validated anti-inflammatory target; however, the use of PDE4 inhibitors is often limited by adverse effects such as nausea, vomiting, and diarrhea. The natural compound braylin was previously identified as a novel PDE4 inhibitor scaffold, exhibiting an IC50 of 0.96 \u00b5M. Using the PDE4\u2013braylin co-crystal structure, we conducted structure-based design and optimization to enhance its potency. Methods: A series of novel braylin derivatives was synthesized and characterized. Their inhibitory activities against PDE4D were evaluated via enzymatic assays, and binding thermodynamics were analyzed by isothermal titration calorimetry (ITC). Molecular modeling was used to predict binding modes, and anti-inflammatory effects were assessed in LPS-stimulated macrophages. Results: Structure-guided optimization yielded lead compound L27, which showed significantly improved PDE4D inhibition (IC50 = 67 nM) and high-affinity binding (Kd = 45 nM) as confirmed by ITC. L27 also exhibited remarkable selectivity against PDE isoforms. Molecular simulations highlighted key interactions with Gln369 and hydrophobic residues in the PDE4 active site. In cellular assays, L27 dose-dependently suppressed LPS-induced inflammation in macrophages at non-cytotoxic concentrations with efficacy comparable to roflumilast. Conclusions: We developed L27, a potent and selective PDE4 inhibitor derived from natural braylin. It demonstrated promising in vitro anti-inflammatory activity and represents a valuable lead for further therapeutic development.<\/jats:p>","DOI":"10.3390\/pharmaceutics18050516","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:43:51Z","timestamp":1777448631000},"page":"516","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Evaluation of Braylin Derivatives as Novel PDE4 Inhibitors with Anti-Inflammatory Effects"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3126-2315","authenticated-orcid":false,"given":"Yongdan","family":"Guo","sequence":"first","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, 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