Synthesis and biological evaluation of new substituted thioglycolurils, their analogues and derivatives

摘要

Abstract A novel series of substituted N -aminothioglycolurils was synthesized by tandem hydrazone formation – ring contraction reaction of 3-thioxoperhydroimidazo[4,5- e ]-1,2,4-triazin-6-ones with ( E )-3-phenyl(furan-2-yl)acrylaldehyde derivatives. S -Alkyl substituted N -aminothioglycolurils were prepared through alkylation of corresponding thioglycolurils with iodoalkane or 4-chlorobenzylchloride. Methylthio group in S -methyl derivatives can be substituted with hydroxyl group in acid medium to give N -aminoglycolurils. Representative compounds were evaluated for their cytotoxic activity against RD, A549, HCT116 and MCF7 human cancer cell lines by MTT-assay and screened for their antifungal activity against phytopathogenic fungi using the mycelium growth inhibition method in?vitro . Among the derivatives, 4-(( E )-(( E )-3-(2-Methoxyphenyl)allylidene)amino)-3-methyl-1-phenylthioglycoluril 8i was found to have the highest antiproliferative activity toward the RD and HCT116?cell lines ( 8i : IC 50 ?=?0.02 and 0.012?μM, respectively), which exceeded cytotoxicity of reference drugs. 1,3-Diethyl-4-(( E )-(( E )-3-(2-methoxyphenyl)allylidene)amino)thioglycoluril 8l showed the most marked activity toward A549?cells ( 8l : IC 50 ?=?0.61?μM) compared to reference drugs. The IC 50 values of thioglycolurils 8i,l against normal human embryonic kidney cells HEK293 were 0.23 and 86.11?μM, respectively, exceeding the IC 50 values of this compound toward the RD, HCT116 ( 8i ) and A549?cells ( 8l ) by one-two orders of magnitude. Experiments with annexin showed that compounds 8b,i,l induced apoptosis in Jurkat cells (acute T cell leukemia). Alkylthioderivatives 12a,13a displayed the strongest antifungal action against R.?solani , F.?oxysporum , and F.?moniliforme exceeding those of triadimefon. Graphical abstract Display Omitted Highlights ? Focused library of 51 novel imidazo[4,5- d ]imidazoles were synthesized. ? Antiproliferative activity of compounds was assessed on cancer cell lines. ? Compound 8i was more potent than reference drugs on three of four cancer cell lines. ? Compounds 8b,l treated Jurkat cells have a high percentage of apoptotic population. ? Antifungal activity of compounds was assessed on six phytopathogenic fungi.