Synthesis, cytotoxic evaluation, molecular docking, and DFT analysis of 1,3,4-thiadiazole-2,5-dithiol derivatives.

Abstract

A new series of 1,3,4-thiadiazole-2,5-dithiol-based acetohydrazide derivatives 6a-f has been designed and synthesized via a multi-step procedure that includes esterification and condensation reactions. Target compounds 6a-f were synthesized using various substituted aryl aldehydes and hydrazide intermediate 3. FT-IR, 1H NMR and 13C NMR spectroscopy, and elemental analysis were used to characterize the synthesized compounds. The cytotoxic activity of the target compounds 6a-f against Caco-2 colorectal cells was evaluated at different concentrations using the MTT assay. The results showed that derivative 6a, which has a p-NO2 group on the phenyl ring, displayed good activity with an IC50 of 262.5 µg/mL. Molecular docking studies of compound 6a revealed a remarkable binding affinity towards HDAC1 and FGFR, with docking scores of -7.7 and -9.3 kcal/mol, respectively, facilitated by several hydrogen bonds and hydrophobic interactions. The DFT analysis revealed a high energy gap (9.882 eV), indicating good electronic stability, moderate electrophilicity, and significant molecular polarity, suggesting a favorable interaction potential in biological settings. Additionally, the drug-likeness and ADMET properties of the lead compound were predicted to be favorable based on in silico drug-likeness and ADMET evaluations.