Rippel, RafaelLeitão, FláviaGeorgieva, Miglena K.Mamede, RafaelGomes, Clara S. B.Roma-Rodrigues, CatarinaFernandes, Alexandra R.Lourenço, AnaFerreira, Luísa M.Branco, Paula S.2024-05-222024-05-222024-03-181144-0546PURE: 85886390PURE UUID: 1bc78714-4a3a-4e9f-9933-374e16d89979Scopus: 85186993310WOS: 001176071500001ORCID: /0000-0003-0839-4123/work/168299711ORCID: /0000-0003-2054-4438/work/168299778ORCID: /0000-0003-3672-0045/work/168299869ORCID: /0000-0002-7312-8596/work/168300040ORCID: /0000-0001-8474-3925/work/168300141ORCID: /0000-0001-7358-3428/work/168300316http://hdl.handle.net/10362/167645C. S. B. Gomes acknowledges the XTAL – Macromolecular Crystallography group (UCIBIO and i4HB) for granting access to the X-ray diffractometer. X-Ray infrastructure was financed by FCT-MCTES through project RECI/BBBBEP/0124/2012. Publisher Copyright: © 2024 The Royal Society of Chemistry.A novel approach has been developed for the efficient synthesis of the unsymmetrical (2-aminopyrrolidin-1-yl)carboxamidine alkaloidal core found in cernumidine (1) and its analogs (20a, 20c, 20f, 20i-o). The key transformation in this process involves the utilization of the Curtius rearrangement, which plays a pivotal role in constructing the aminal moiety. One of the major challenges encountered during this synthesis was the instability of the free aminal core intermediate. Furthermore, a noteworthy observation during the synthesis was the racemization process that occurred during the isocyanate trapping by organometallic reagents. Detailed DFT calculations shed light on this phenomenon, revealing a neighboring coordination-induced mechanism. The resulting compounds were subjected to evaluation for their anti-inflammatory properties using lipopolysaccharide-stimulated human THP1 cells. Notably, compounds featuring the guanidine moiety and electron-donating groups exhibited significant anti-inflammatory activity. These findings suggest that these compounds hold promise as potential candidates for further development as anti-inflammatory agents.112156574engCatalysisGeneral ChemistryMaterials Chemistryjournal article10.1039/d3nj05406chttps://www.scopus.com/pages/publications/85186993310