Synthesis and characterization of selected new thiazolidine-2,4-diones derivatives: SwissADME and density-functional-theory analysis

Abstract

The synthesis of novel thiazolidine-2,4-dione derivatives, their pharmacokinetic profile, and their structural features for drug-like potential are all covered in the current work. Thiazolidine-2,4-dione was selected as a core scaffold due to its well-established role as a privileged pharmacophore in antidiabetic drug discovery, primarily through PPAR-γ activation, along with its known structural flexibility that allows diverse substitutions for optimization of biological and pharmacokinetic properties. The compounds were synthesized by chemically treating 4-nitrobenzaldehyde, nitro group was converted to an amine under the specific conditions of the Knoevenagel reaction. Compounds were future modification produces the target molecules compound 1 to compound 5 (C1–C5) followed by characterization via spectroscopy techniques including ¹H-NMR and ¹³C-NMR. Unlike previously reported thiazolidine-2,4-dione derivatives, including our earlier series, the present study introduces structurally diversified analogues with varied electron-donating and electron-withdrawing substituents designed to improve drug-likeness, metabolic stability, and pharmacokinetic behavior. In silico ADME (absorption, distribution, metabolism, and excretion) investigations were conducted using SwissADME software. The DFT/TDFT (Density functional theory) tool explored various properties of molecules, including electronic and physicochemical excited-state properties. SwissADME shows that Lipinski’s rule of five was followed all compounds except C3, with overall promising GI absorption. However, derivatives failed to cross the blood-brain barrier and para-glycoprotein substrates except C2 and C4. In drug metabolism analysis, no effect on CYP2D6 was noted. DFT/TDFT analysis of C1–C5 explored various properties of the test molecules and suggested their overall chemical stability, pharmacological activity, and therapeutic potential. In conclusion, all newly synthesized thiazolidine-2,4-dione derivatives showed encouraging therapeutic potential according to in silico studies, suggesting that they might be a possible therapeutic target.