Design, synthesis, and development of 4-(4-Fluorobenzyl)piperazine–acetanilide conjugates as novel tyrosinase inhibitors
Bioorganic Chemistry, cilt.181, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 181
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.bioorg.2026.110284
- Dergi Adı: Bioorganic Chemistry
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Academic Search Ultimate (EBSCO)
- Anahtar Kelimeler: 4-(4-fluorobenzyl)piperazine, DPPH, Melanin content, Molecular docking, Tyrosinase
- Hacettepe Üniversitesi Adresli: Evet
Özet
A series of 4-(4-fluorobenzyl)piperazine derivatives ( 2a–u ) were designed, synthesized, and evaluated as potential tyrosinase inhibitors. In vitro enzymatic assays using L-DOPA as a substrate revealed that several derivatives exhibited higher inhibitory activity than kojic acid under identical experimental conditions. Among them, compounds 2 h (4-NO2) and 2n (2-NO2) were identified as the most active derivatives, with IC50 values of 85.24 and 89.38 μM, respectively, compared with 206.42 μM for kojic acid. Structure-activity relationship analysis revealed that a short methylene linker, nitro substitution, and limited steric bulk were favorable for tyrosinase inhibition. Molecular docking studies supported these findings by demonstrating favorable interactions of the active compounds with key residues within the tyrosinase binding pocket. The biological profile of compound 2 h was further investigated through melanin content, cytotoxicity, and antioxidant activity assays. Melanin content studies revealed concentration-dependent biphasic effects on melanogenesis, while cytotoxicity assays demonstrated low toxicity toward 3 T3 cells. DPPH radical scavenging experiments indicated weak antioxidant activity for both compound 2 h and kojic acid. Overall, the combined biological, SAR, and molecular docking results identify compound 2 h as a promising lead structure for the further development of tyrosinase inhibitors.