Sustainable Synthesis of Novel Hydroxylated Tranilast Analogues and Their Bioactivities

Tranilast, an anti-allergic drug with well-established anti-inflammatory, antifibrotic, and antiproliferative properties, suffers from poor water solubility and low bioavailability, which limit its therapeutic potential. To improve its pharmacological profile, we designed and synthesized a novel series of hydroxylated Tranilast analogues. The compounds were obtained through a green, single-step coupling reaction between activated methoxy-substituted hydroxycinnamic acids and anthranilic or hydroxyanthranilic acids, using a triethylamine–isobutyl chloroformate system in environmentally friendly solvents. Fifteen derivatives were isolated in good to excellent yields (63–94%) without chromatographic purification. The synthesized compounds were evaluated for antimicrobial, antioxidant, anti-inflammatory, and antiproliferative activities. Several analogues displayed notable antimicrobial effects against Candida albicans, Staphylococcus aureus, and Klebsiella pneumoniae, with minimum inhibitory concentrations as low as 75 µg/mL. Hydroxylated derivatives showed enhanced radical-scavenging activity in DPPH and ABTS assays compared with Tranilast. Selected compounds also demonstrated suggestive antiproliferative effects against LNCaP prostate cancer cells while maintaining low cytotoxicity toward HaCaT keratinocytes, indicating favourable selectivity. Furthermore, some derivatives significantly reduced nitric oxide production in LPS-stimulated HaCaT cells, confirming their anti-inflammatory potential. Overall, hydroxylation proves to be an effective strategy for improving the biological profile of Tranilast, yielding promising candidates for further pharmacological development.