Anti-inflammatory and Antimicrobial Properties of Ibuprofen Analogues Derived by Photoredox-Catalyzed C-N Scission of Tertiary Amines and Amidation.

This manuscript describes the synthesis of ibuprofen-derived amides, and their biological evaluation with respect to anti-inflammatory and antimicrobial properties, including inhibition of biofilm formation. The compounds were synthesized using a previously developed photoredox-catalyzed protocol, which proceeds through C-N bond scission of the tertiary amine building blocks, followed by in situ amide coupling; thus, 16 derivatives of ibuprofen were prepared on 30 to 70 mg scales. Evaluation in multiple antimicrobial and biofilm-related biological assays revealed desired activities for many of the compounds. Compounds 9-11 and 14-16 are newly synthesized in the literature, compounds 1-8 have been previously reported by us, and compounds 12-13 are known in the literature. The broad-spectrum antimicrobial activities of all molecules were evaluated for the first time in these studies. An initial phenotypic screening under inflammatory stress was performed using an MTT-based LPS challenge model, which revealed that several derivatives (2, 4, 7, and 11-16) preserved cell viability more effectively than ibuprofen. Based on these findings, selected compounds were further evaluated using direct biochemical assays, demonstrating that ibuprofen amide derivatives significantly suppressed LPS-induced production of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6 in RAW 264.7 macrophages. Assessment of antimicrobial activity against Escherichia coli, MRSA, and Candida albicans demonstrated notable inhibitory activities by compounds 15 and 16. The same compounds also showed inhibition of biofilm growth. Collectively, these results demonstrate that photoredox-catalyzed modification of the ibuprofen scaffold enables rapid access to newly synthesized analogues combining confirmed anti-inflammatory activity with antimicrobial and antibiofilm properties.