Semi-synthetic approaches to bile acids and preclinical evaluation of chenodeoxycholic acid in acute and chronic cutaneous inflammation with docking insights

Bile acids are a major class of compounds derived from cholesterol catabolism and have been linked to diverse biological activities, including anti-inflammatory, anticancer, antimicrobial, antifungal, and neuroprotective effects. In this study, chenodeoxycholic acid (CDCA), three new CDCA hybrids bearing with 1,2,3-triazole ring at C-3 and C-24 positions, two different C-24 esters, as well as a C-3 azide semisynthetic derivatives were evaluated for their effects on acute TPA-induced ear edema in mice. The results demonstrate that CDCA and its derivatives exhibit topical anti-inflammatory properties. However, the 1,2,3-triazole-linked CDCA hybrids did not present topical anti-inflammatory activity. The anti-inflammatory effects of CDCA (50 mg/kg p.o.) were similar to those of indomethacin (8 mg/kg p.o.) in models of acute and chronic TPA-induced ear edema. Molecular docking indicated that CDCA may interact with multiple molecular targets, including the nuclear receptor FXR, inflammatory mediators (TNF-α and IL-1β), and the transcriptional regulator NF-κB p65. End-point free-energy calculations (MM/GBSA) supported these trends, supporting the possibility of interactions with multiple inflammation-related targets. These in vivo and computational studies provide an experimental follow-up to consider CDCA as a scaffold for multi-target modulation within metabolic and inflammatory pathways.