biostudies-literatureLin ACKThe Second Century Fund (C2F), Chulalongkorn UniversityThailand Science Research and Innovation Fund20858https://www.ebi.ac.uk/biostudies/studies/S-EPMC9718795biostudies-literatureUnknown12(1)Caffeic acid derivatives containing amide moieties similar to those of finasteride and dutasteride were synthesized. An in vitro inhibitory activity evaluation of caffeic acid (1) and its amide derivatives (2 - 4) against the steroid 5α-reductase type 1 (SRD5A1) produced by human keratinocyte cells coupled with the non-radioactive high-performance thin-layer chromatography detection revealed that caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide (4) was a promising non-steroidal suppressor, with a half-maximal inhibitory concentration (IC₅₀) of 1.44 ± 0.13 µM and relatively low cytotoxicity with an IC₅₀ of 29.99 ± 8.69 µM. The regulatory role of compound 4 against SRD5A1 involved both suppression of SRD5A1 expression and mixed mode SRD5A1 inhibition. The K_i value of compound 4 was 2.382 µM based on the whole-cell kinetic studies under specific conditions. Molecular docking and molecular dynamics simulations with AlphaFold generated the human SRD5A1 structure and confirmed the stability of compound 4 at the SRD5A1 catalytic site with greater interactions, including hydrogen bonding of the key M119 amino-acid residue than those of finasteride and dutasteride. Thus, compound 4 shows the potential for further development as an SRD5A1 suppressor for androgenic alopecia treatment.Scientific reportsCaffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics.PMC9718795CU_FRB640001_23_33_8Netcharoensirisuk PChansriniyom CChaotham CDe-Eknamkul WSukma WRungrotmongkol TSanachai KLin ACKChamni SfalseCaffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics.Caffeic acid derivatives containing amide moieties similar to those of finasteride and dutasteride were synthesized. An in vitro inhibitory activity evaluation of caffeic acid (1) and its amide derivatives (2 - 4) against the steroid 5α-reductase type 1 (SRD5A1) produced by human keratinocyte cells coupled with the non-radioactive high-performance thin-layer chromatography detection revealed that caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide (4) was a promising non-steroidal suppressor, with a half-maximal inhibitory concentration (IC₅₀) of 1.44 ± 0.13 µM and relatively low cytotoxicity with an IC₅₀ of 29.99 ± 8.69 µM. The regulatory role of compound 4 against SRD5A1 involved both suppression of SRD5A1 expression and mixed mode SRD5A1 inhibition. The K_i value of compound 4 was 2.382 µM based on the whole-cell kinetic studies under specific conditions. Molecular docking and molecular dynamics simulations with AlphaFold generated the human SRD5A1 structure and confirmed the stability of compound 4 at the SRD5A1 catalytic site with greater interactions, including hydrogen bonding of the key M119 amino-acid residue than those of finasteride and dutasteride. Thus, compound 4 shows the potential for further development as an SRD5A1 suppressor for androgenic alopecia treatment.2022-01-01T00:00:00Z2022 Dec2026-05-28T01:10:58.977Z2025-04-19T22:48:54.302ZS-EPMC97187953646072910.1038/s41598-022-25335-7