Design, Integrated Structural, and Theoretical Investigation of a Novel 4-Fluoro Derivative Targeting Sirtuin-1

Abstract

Thiazolidin-4-one (TZD) heterocycles are gaining attention as potential anticancer agents. Combining TZDs with various scaffolds can enhance therapeutic impact and achieve polypharmacological outcomes. This study investigates the solid-state properties and spectral analysis of a new fluorinated TZD derivative, 3-N-(4-fluorophenyl)-2-N'-(4-fluorophenylimino)-thiazolidin-4-one (NFFT). This compound features two fluorophenyl substitutions on the TZD core; its structure was confirmed through single-crystal X-ray diffraction (SC-XRD), showing orthorhombic crystallization in the Pca2(1) space group. Additional spectroscopic techniques supported the structural elucidation, including 1H and 13C NMR, FT-IR, and UV-vis. Analyses using Hirshfeld surface and reduced density gradient (RDG) revealed meaningful non-covalent interactions affecting crystal packing. Density functional theory (DFT) calculations at the B3LYP/6-311++G(d,p) level confirmed the experimental geometry and provided insights into electronic properties via frontier molecular orbital (FMO) analysis and global reactivity descriptors. Molecular docking studies against the sirtuin-1 (SIRT1) protein, known for its complex role in cancer proliferation, potentially acting as a tumor promoter in prostate, breast, and liver cancers, were conducted using NFFT. The latter showed favorable binding interactions, highlighting its potential as SIRT1 inhibitor. According to Lipinski's rule of five, NFFT is expected to have drug-like properties.