Abstract
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.