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 <b>9</b>-<b>11</b> and <b>14</b>-<b>16</b> are newly synthesized in the literature, compounds <b>1</b>-<b>8</b> have been previously reported by us, and compounds <b>12</b>-<b>13</b> 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 (<b>2</b>, <b>4</b>, <b>7</b>, and <b>11</b>-<b>16</b>) 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 <i>Escherichia coli</i>, MRSA, and <i>Candida albicans</i> demonstrated notable inhibitory activities by compounds <b>15</b> and <b>16</b>. 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.