Synthesis, Molecular Docking, and Antitumor Activity of 1,3,4‐Thiadiazole‐Based Heterocycles against Hepatocellular Carcinoma

Abstract Numerous aminothiadiazole‐based compounds have been extensively employed as pharmaceuticals to treat a variety of ailments, leading to a flurry of new discoveries. It takes novel synthetic techniques to prepare new aminothiadiazole derivatives from enaminonitrile derivative 4 , which was formerly an important step in the synthesis of pyrazole, isoxazole, and pyrimidine derivatives ( 6 , 8 , and 10 ). For the production of triazolo, imidazolo, and pyrazolo pyrimidine derivatives, enaminonitrile 4 also has shown chemical activity toward various N ‐nucleophiles, such as heterocyclic amines ( 12 , 14 , and 16 ). As a result of cyclo‐condensing enaminonitrile precursor 4 with a variety of carbon and oxygen nucleophiles, certain complex, polyfunctional substituted fused 2‐pyridone and chromenone derivatives containing thiadiazole molecules were produced ( 18 , 20 , 22 , and 25 ). Next, the cytotoxic effect of the entitled compounds against HepG2 and MCF7 has been reported, followed by an in‐vivo study on hepatocellular carcinoma (HCC) HepG2 with the compounds that showed the lowest IC 50 values. In addition to molecular docking into the FGFR 4 active site (PDB: 4XCU), the bioavailability of the active compounds in accordance with Lipinski's rule of five has been shown.