Diethylene Glycol‐Linked Ring‐Fused Bis‐Azoles: Target‐Oriented Synthesis, In Silico Screening, and Antitumor Activity

The target‐oriented synthesis of diethylene glycol‐linked bis‐imidazo‐ and bis‐thiazolo ring‐fused mono‐, bi‐, and tricyclic derivatives was accomplished using inexpensive reagents, bis‐phenacyl bromide derivative 4 , and thiosemicarbazone 6 . The diethylene glycol‐linked architectures included bis(thiazolo[3,2‐ a ]pyrimidinone) derivatives 8a,b , bis(imidazo‐azole) derivatives 12‐14 , bis(imidazo‐thiazole) derivatives 17,18 , and bis‐thiazoles 20a‐g . Cytotoxic evaluation against liver, lung, colon, and prostate human tumor cell lines found remarkable selectivity to hepatocellular carcinoma (HepG2) cells. The most potent bis‐imidazo‐ and bis‐thiazolo‐fused derivatives 8a,b , 12 and 13 demonstrated cytotoxicity against HepG2 cells (IC ₅₀ 6.8–17.8 µM) with exceptional selectivity (SI 5.6–14.6) compared with cisplatin (SI 2.4). Further screening of their VEGFR‐2 TK and FGFR‐2 TK inhibition showed that 8a had moderate activity, whereas phenyl‐substituted derivative 8b displayed promising anti‐VEGFR‐2 and remarkable anti‐FGFR‐2 activities, with IC ₅₀ 0.19 ± 0.01 and 0.03 ± 0.01 µM, respectively, compared with the reference drugs sorafenib (IC ₅₀ 0.12 ± 0.01) and staurosporine (IC ₅₀ 0.03 ± 0.01 µM). The inhibition of VEGFR‐2 and FGFR‐2 TKs was supported by molecular docking studies, with compound 8b showing binding affinity to the VEGFR‐2 and FGFR‐2 ATP binding pockets. Pharmacokinetics and ADMET drug‐likeness evaluation indicated that bis(thiazolo[3,2‐ a ]pyrimidinone) derivatives 8a and 8b have drug‐like properties.