Synthesis of Tryptamine-Thiazolidin-4-one Derivatives and the Combined In Silico and In Vitro Evaluation of their Biological Activity and Cytotoxicity

Tryptamine, a monoamine alkaloid with an indole ring structure, is derived from the decarboxylation of the amino acid tryptophan, which is present in fungi, plants, and animals. Tryptamine analogues hold significant therapeutic potential due to their broad pharmacological activities, including roles as neurotransmitters and potential therapeutic agents for various diseases. Structural modifications of tryptamine enhance receptor selectivity and metabolic stability, improving therapeutic efficacy. These modifications are crucial for optimizing pharmacokinetic and pharmacodynamic properties, making the analogues more effective and safer for clinical use. In this study, novel tryptamine-thiazolidin-4-one (YS1-12) derivatives were synthesized via a one-pot three-component condensation reaction. The synthesized compounds are characterized by different spectroscopy techniques such as FT-IR, ¹H NMR, ¹³C NMR, and HR-NMS. The synthesized compounds were subjected to binary QSAR disease models for bioactivity prediction and a target prediction model for target analysis. Potential targets were identified, and physics-based molecular simulations were conducted. Additionally, MM/GBSA binding free energy analysis was performed to calculate the average binding free energies of YS1-12 compared to reference molecules. Our computational results indicated promising biological activities for these new compounds. To further investigate these activities, the compounds were tested in vitro using two different cancer cell lines: YKG-1 glioblastoma and SH-SY5Y neuroblastoma cells. The results confirmed the potential activities of these novel compounds. Notably, compounds YS4 and YS10 exhibited favorable activities compared to the control compounds 5-FU and Temozolomide. YS4 demonstrated an IC₅₀ value of 20 nM against YKG-1 cells, while YS10 exhibited an IC₅₀ value of 0.44 nM against SH-SY5Y cells.