Natural Product-Inspired Bis(trifluoromethyl) Phenyl Hydroxycinnamate Derivatives as Promising Nonsteroidal Inhibitors of Human Steroid 5α-Reductase Type-1: Synthesis, <i>In Vitro</i>, and <i>In Silico</i> Studies
Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide The development of steroid 5α-reductase inhibitors for the treatment of androgenetic alopecia remains challenging, primarily due to the unavailability of a crystal structure for human steroid 5α-reductase type-1 (SRD5A1) and the adverse effects associated with existing steroidal therapeutic agents such as finasteride and dutasteride. In this study, hydroxycinnamate derivatives were synthesized and evaluated for their inhibitory activity against SRD5A1 using an immortalized human keratinocyte cell-based assay coupled with nonradioactive high-performance thin-layer chromatography analysis. Three ferulate derivatives featuring 2′,5′-, 3′,4′-, and 3′,5′-bis(trifluoromethyl)phenyl substituents ( 10a, 10b, and 10c ) demonstrated inhibitory activity with half-maximal inhibitory concentrations (IC 50 ) of 8.50, 10.06, and 8.05 μM, respectively, exhibiting low cytotoxicity and favorable predicted lipophilicity. Compound 10a was chosen for further investigation to assess its effect on SRD5A1 protein expression. Treatment of HaCaT cells with compound 10a at concentrations of 10–15 μM for 24 h significantly downregulated SRD5A1 protein expression, suggesting its inhibitory effect on both SRD5A1 activity and expression. An in silico model identified key binding interactions between the AlphaFold-generated SRD5A1 catalytic pocket and the residues R98, M119, A120, E202, and F228, among which M119 is recognized as a crucial residue for the stereoselective and irreversible reduction catalyzed by SRD5A1. Structure–activity relationship analysis indicated that the 3-methoxy-4-hydroxy core facilitates hydrogen bonding with R98, whereas the cinnamoyl and bis(trifluoromethyl)phenyl moieties enhance hydrophobic and halogen interactions with key residues, improving binding affinity and molecular orientation. Thus, these bis(trifluoromethyl)-substituted phenyl ferulate derivatives present a promising class of nonsteroidal inhibitors for SRD5A1, with potential applications in developing topical antiandrogenic agents for the treatment androgen-related conditions.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".