Novel Thioether‐Bridged 2,6‐Disubstituted and 2,5,6‐Trisubstituted Imidazothiadiazole Analogues: Synthesis, Antiproliferative Activity, ADME, and Molecular Docking Studies

Abstract In this study, starting from 2‐amino‐1,3,4‐thiadiazole derivatives ( 3 – 5 ), a new series of 2,6‐disubstituted (compounds 7 – 15 ) and 2,5,6‐trisubstituted (compounds 16 – 33 ) imidazo[2,1 ‐b ][1,3,4]‐thiadiazole derivatives were synthesized using cyclization and Mannich reaction mechanisms, respectively. All synthesized compounds were characterized by 1 H‐NMR, 13 C‐NMR, FT‐IR, elemental analysis, and mass spectroscopy techniques. Also, X‐ray diffraction analysis were used for compounds 4 , 7 , 11 , 17 , and 19 . The cytotoxic effects of the new compounds on the viability of colon cancer cells (DLD‐1), lung cancer cells (A549), and liver cancer cells (HepG2) were investigated using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) method in vitro . Compound 15 was found to be the most potent anticancer drug candidate in this series with an IC 50 value of 3.63 μM against HepG2 for 48 h. Moreover, the absorption, distribution, metabolism, and excretion (ADME) parameters of the synthesized compounds were calculated and thus, their potential to be safe drugs was evaluated. Finally, to support the biological activity experiments, molecular docking studies of these compounds were carried out on three different target cancer protein structures (PDB IDs: 5ETY, 1M17, and 3GCW), and the amino acids that play key roles in the binding of the compounds to these proteins were determined.