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

被引:29
作者
Gazieva, Galina A. [1 ]
Anikina, Lada V. [2 ]
Nechaeva, Tatyana V. [1 ,3 ]
Pukhov, Sergey A. [2 ]
Karpova, Tatyana B. [1 ]
Popkov, Sergey V. [3 ]
Nelyubina, Yulia V. [4 ]
Kolotyrkina, Natalya G. [1 ]
Kravchenko, Angelina N. [1 ]
机构
[1] Russian Acad Sci, ND Zelinsky Inst Organ Chem, Moscow 119991, Russia
[2] Russian Acad Sci, Inst Physiol Act Cpds, Chernogolovka 142432, Russia
[3] D Mendeleev Univ Chem Technol Russia, Moscow 125047, Russia
[4] Russian Acad Sci, AN Nesmeyanov Inst Organoelement Cpds, Moscow 119991, Russia
关键词
3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones; Tandem reaction; Ring contraction; Thioglycolurils; Cytotoxic activity; Antifungal activity; RING CONTRACTION; FUNGICIDAL ACTIVITIES; APOPTOSIS;
D O I
10.1016/j.ejmech.2017.09.009
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 iodoallcane 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: IC50 = 0.02 and 0.012 mu M, respectively), which exceeded cytotoxicity of reference drugs. 1,3-Diethyl-4-((E)-((E)-3-(2-methoxyphenyl)allylidene)amino)thioglycoluril 81 showed the most marked activity toward A549 cells (8I: IC50 = 0.61 mu M) compared to reference drugs. The IC50 values of thioglycolurils 8i,I against normal human embryonic kidney cells HEK293 were 0.23 and 86.11 01, respectively, exceeding the IC50 values of this compound toward the RD, HCT116 (8i) and A549 cells (8I) by one-two orders of magnitude. Experiments with annexin showed that compounds 8b,i,I 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. (C) 2017 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:141 / 154
页数:14
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