Synthesis, characterization, and derivatization of some novel types of fluorinated mono- and bis-imidazolidineiminothiones with antitumor, antiviral, antibacterial, and antifungal activities

A series of thirty eight novel imidazolidineiminothiones (6a–g, 10a–h, 13a,b, 15a–d, and 16a), 5-thioxoimidazolidine-2,4-diones (7a–d, 11a–e, 14a,b, and 16b), and bis-imidazolidineiminothiones (17–20) with various fluorinated aromatic substituents at N-(1) and N-(3) were prepared in 75–85% yields. The imidazolidineiminothiones were synthesized from fluorinated N-arylcyanothioformanilides and substituted aromatic isocyanates, and by the reactions of fluorinated aromatic isocyanates with fluorinated and non-fluorinated aromatic N-arylcyanothioformanilides. Subsequent hydrolysis of selected products produced the corresponding 5-thioxoimidazolidine-2,4-diones. Preliminary screening of several compounds against Ehrlich ascites carcinoma (EAC) cells indicated that 6f and 16a were the most active (90% and 80% inhibition, respectively). Further evaluation for cytotoxicity against other tumor cell lines gave IC50 values ranging from 0.67 to 3.83 μg/mL, where compounds 15a and 16a were markedly active against all cell lines. This highlights the synergistic effect of the suitably positioned fluorinated substituents on N-(1) and N-(3) of the imidazolidineiminothiones. Compounds 6a,e–g, 10a–c, 13b, 15a–d, and 17–20 were tested against microbial organisms (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Salmonella typhi, and Sarcina lutea), and fungal strains (Candida albicans, Aspergillus niger, and Aspergillus flavus). Whereas compound 6a exhibited the highest antibacterial activity against Gram positive and Gram negative bacteria, 13b displayed the strongest antifungal activity against all fungal strains, reaching as high as 30 mm. Finally, 15a,b,d were subjected to in vitro testing of antiviral activity against hepatitis A virus (HAV), human herpes simplex virus 1 (HSV1), and Coxsackie B4 (COxB4) viral strain, where 15b was the most effective, reducing virus plaque count of HSV1 and COxB4 by 50% and 60%, respectively.

Graphical abstractA series of novel fluorinated imidazolidineiminothiones, 5-thioxoimidazolidine-2,4-diones, and bis-imidazolidineiminothiones with various substituents at N-(1) and N-(3) were synthesized. In vitro biological evaluation of such compounds showed significant antitumor, antiviral, antibacterial, and antifungal activities.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Fluorinated imidazolidineiminothiones, 5-thioxoimidazolidine-2,4-diones, and bis-imidazolidineiminothiones were prepared. ► They exhibited strong activities against various tumor cell lines, bacterial, fungal, and viral strains. ► Comparison of activities within some groups illustrated the effect exerted by the fluorine, N-(1), and N-(3) substituents. ► Structure–activity studies revealed synergistic and opposing effects between the fluorinated N-(1) and N-(3) substituents.