Natural Product-Inspired Bis(Trifluoromethyl) Phenyl Hydroxycinnamate Derivatives as Promising Nonsteroidal Inhibitors of Human Steroid 5α-Reductase Type-1: Synthesis, In Vitro, and In Silico Studies

This study explores the development of nonsteroidal inhibitors for human steroid 5α-reductase type-1 (SRD5A1) to treat androgenetic alopecia, focusing on hydroxycinnamate derivatives. Three ferulate derivatives, 10a, 10b, and 10c, showed promising inhibitory activity with IC50 values of 8.50, 10.06, and 8.05 μM, respectively, and low cytotoxicity. Compound 10a notably downregulated SRD5A1 protein expression in HaCaT cells, indicating its potential as an effective inhibitor. An in silico model revealed key binding interactions within the SRD5A1 catalytic pocket, highlighting the importance of specific residues and structural features for binding affinity. These findings suggest that bis(trifluoromethyl)-substituted phenyl ferulate derivatives could be promising candidates for developing topical antiandrogenic treatments.