{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T22:22:47Z","timestamp":1787869367816,"version":"build-2784847793"},"reference-count":49,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Council of Science, Humanity and Technology (CONAHCyT) Project","award":["2018-02-01-119092"],"award-info":[{"award-number":["2018-02-01-119092"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: The development of specific inhibitors for cyclooxygenase-2 (COX-2) is a challenge for public health. A series of 17 N-phthalimide hybrids was evaluated using a functional M06 meta-GGA hybrid in combination with a polarized 6-311G (d, p) basis set. The top three candidates (6, 10, and 17) were synthesized and evaluated as selective COX-2 inhibitors of PGE-2 using an integrated in silico\u2013in vitro approach. Methods: Molecular docking against COX-2 (PDB 5KIR) and COX-1 (PDB 6Y3C), supported by homology modeling and DFT geometry optimization (B3LYP\/6-31G*), revealed that the phthalimide carbonyl groups and the 3,4,5-trimethoxyphenyl or geranyl-derived moieties establish key hydrogen bonds and hydrophobic contacts with Arg120, Tyr355, Tyr385, and Ser530 in the COX-2 active site, conferring predicted selectivity \u0394GCOX\u22122 vs. COX\u22121 = \u22121.4 to \u22122.8 kcal\/mol. Results: The compounds complied with Lipinski\u2019s and Veber\u2019s rules and displayed favorable ADMET profiles. In vitro assessment in LPS-stimulated J774A.1 murine macrophages confirmed potent inhibition of PGE2 production, 3.05 \u00b5g\/mL, with compound 17 exhibiting the highest efficacy, 97.79 \u00b1 5.02% inhibition at 50 \u00b5g\/mL, and 10 showing 95.22 \u00b1 6.03% inhibition at 50 \u00b5g\/mL. Notably, all derivatives maintained &gt;90% cell viability up to 250 \u00b5g\/mL by resazurin assay and showed no evidence of cytotoxicity or mitosis potential in the tests at 24 h. Conclusions: These results demonstrate that strategic hybridization of phthalimide with natural and synthetic product-derived fragments yields highly potential PGE2 inhibitors. Therefore, compounds 6, 10, and 17 are promising lead candidates for the development of safer anti-inflammatory agents.<\/jats:p>","DOI":"10.3390\/pharmaceutics18010129","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T14:57:58Z","timestamp":1768921078000},"page":"129","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Phthalimide Derivatives as Anti-Inflammatory Agents: In Silico COX-2 Targeting and In Vitro Inhibition of PGE2 Production"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2029-0848","authenticated-orcid":false,"given":"H\u00e9ctor M.","family":"Heras Mart\u00ednez","sequence":"first","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Universidad Aut\u00f3noma de Chihuahua, Chihuahua 31125, Mexico"},{"name":"Department of Chemistry and Physics, Florida Gulf Coast University, Fort Myers, FL 33965, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7284-7855","authenticated-orcid":false,"given":"Blanca","family":"S\u00e1nchez-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Universidad Aut\u00f3noma de Chihuahua, Chihuahua 31125, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7240-1458","authenticated-orcid":false,"given":"Linda-Lucila","family":"Landeros-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Universidad Aut\u00f3noma de Chihuahua, Chihuahua 31125, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6975-2093","authenticated-orcid":false,"given":"David","family":"Rodr\u00edguez-Guerrero","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Universidad Aut\u00f3noma de Chihuahua, Chihuahua 31125, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 C.","family":"Espinoza-Hicks","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Universidad Aut\u00f3noma de Chihuahua, Chihuahua 31125, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerardo","family":"Zaragoza-Gal\u00e1n","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Universidad Aut\u00f3noma de Chihuahua, Chihuahua 31125, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8504-355X","authenticated-orcid":false,"given":"Alejandro","family":"Bugarin","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Physics, Florida Gulf Coast University, Fort Myers, FL 33965, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6852-0406","authenticated-orcid":false,"given":"David","family":"Ch\u00e1vez-Flores","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Universidad Aut\u00f3noma de Chihuahua, Chihuahua 31125, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Goniewicz, K. 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