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

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 (IC₅₀ 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 IC₅₀ 0.19 ± 0.01 and 0.03 ± 0.01 µM, respectively, compared with the reference drugs sorafenib (IC₅₀ 0.12 ± 0.01) and staurosporine (IC₅₀ 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.