Synthesis, X-ray Crystal Structure, Anticancer, Hirshfeld Surface Analysis, DFT, TD-DFT, ADMET, and Molecular Docking of 3-Phenyl-1,2,4-triazolo[3,4-h]-13,4-thiaza-11-crown-4.

In this work, we describe the synthesis of new macrocycles derived from 3-phenyl-1,2,4-triazole-5-thione in a heterogeneous medium using liquid-solid phase transfer catalysis (PTC) conditions. The structures of the two compounds ( and ) isolated were elucidated based on spectral data (H-NMR, C-NMR) and confirmed in the case of 3-phenyl-1,2,4-triazolo [3,4-h]-13,4--thiaza-11-crown-4 () by a single-crystal X-ray diffraction analysis. Furthermore, the experimental spectral and the X-ray geometrical parameters were compared with their corresponding predicted ones obtained at the B3LYP/6-311++G(d,p) level of theory. The intercontacts between crystal units were investigated through Hirshfeld surface analysis. The drug-like macrocycles were predicted using ADMET and drug-likeness properties, which showed that may act as an inhibitor of DNA-dependent protein kinase (DNA-PK). This assumption was confirmed by the well-binding fitting of into the binding site of DNA-PK and the formation of a stable -DNA-PK complex with a binding energy of -7 kcal-mol. Finally, the anticancer activity of was assessed by an MTT assay against A549 cells, which showed that has moderate anticancer activity compared to that of the doxorubicin reference drug.