Evaluation of Cytocompatibility and Anti-Inflammatory Activity of Carboxyxanthones Selected by In Silico Studies

Carboxyxanthones containing carboxylic acid groups linked to lipophilic aromatic rings resemble the key pharmacophoric features of many nonsteroidal anti-inflammatory drugs (NSAIDs). This structural similarity makes them attractive scaffolds for the development of new anti-inflammatory agents. This study describes the production, cytocompatibility, and anti-inflammatory potential of ten carboxyxanthones (<b>1</b>-<b>10</b>) and two intermediates (<b>11</b>-<b>12</b>) by evaluating their effects on key pro-inflammatory mediators, namely interleukin 6 (IL-6) and prostaglandin E2 (PGE₂). As these compounds are produced by distinct mechanisms, their multi-target potential will be evaluated. Carboxyxanthones were obtained by multi-step pathways using different synthetic approaches through classical benzophenone or diaryl ether intermediates synthesis followed by intramolecular acylation. To the best of our knowledge, the synthesis of carboxyxanthones <b>3</b> and <b>5</b> is described herein for the first time. All tested compounds were cytocompatible with lipopolysaccharide (LPS)-stimulated macrophages. The most notable carboxyxanthones were <b>3</b>, <b>4</b>, <b>7</b>, and <b>8</b>, which were able to significantly reduce IL-6 production by approximately 60%. Molecular docking simulations between compounds <b>1</b>-<b>12</b> and cyclooxygenase-2 were conducted to characterize the structural features underlying molecular recognition, and to identify the most promising candidates for subsequent PGE₂ assays. Carboxyxanthones <b>3</b>, <b>5</b>, and <b>6</b>, as well as intermediate <b>12</b>, were predicted to be the best. In the human in vitro inflammation model used, carboxyxanthone <b>6</b> exhibited the most potent and consistent inhibitory effect on PGE₂ production. At the highest concentration tested (100 µM), it presented an efficacy comparable to that of celecoxib. Carboxyxanthones <b>3</b> and <b>5</b> demonstrated a biphasic effect, decreasing and increasing PGE₂ production at lower (5, 12.5, and 25 µM) and higher (50 and 100 µM) concentrations, respectively. These results highlight the potential of carboxyxanthones as promising modulators of inflammatory pathways, paving the way for further studies aimed at elucidating their mechanisms of action, optimizing structural features, and assessing their safety and therapeutic potential in relevant disease models.