Efficient synthesis, biological evaluation, and docking study of isatin based derivatives as caspase inhibitors

被引:15
作者
Firoozpour, Loghman [1 ]
Gao, Lixin [2 ]
Moghimi, Setareh [1 ]
Pasalar, Parvin [3 ]
Davoodi, Jamshid [4 ]
Wang, Ming-Wei [2 ]
Rezaei, Zahra [5 ]
Dadgar, Armin [6 ]
Yahyavi, Hoda [1 ]
Amanlou, Massoud [5 ]
Foroumadi, Alireza [1 ,5 ]
机构
[1] Univ Tehran Med Sci, Inst Pharmaceut Sci TIPS, Drug Design & Dev Res Ctr, Tehran, Iran
[2] Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China
[3] Univ Tehran Med Sci, Fac Med, Dept Biochem, Tehran, Iran
[4] Univ Tehran, Inst Biochem & Biophys, Tehran, Iran
[5] Univ Tehran Med Sci, Fac Pharm, Dept Med Chem, Tehran, Iran
[6] Kermanshah Univ Med Sci, Pharmaceut Sci Res Ctr, Kermanshah, Iran
基金
美国国家科学基金会;
关键词
Caspase inhibitor; Isatin sulphonamides; docking studies; Pharmacophore; apoptosis; SELECTIVE NONPEPTIDE INHIBITORS; APOPTOSIS; POTENT; DISCOVERY; 4-ARYL-4H-CHROMENES; PET; ACTIVATION; SCAFFOLD; DESIGN; SERIES;
D O I
10.1080/14756366.2020.1809388
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
ABTRACT In this paper, a new series of isatin-sulphonamide based derivatives were designed, synthesised and evaluated as caspase inhibitors. The compounds containing 1-(pyrrolidinyl)sulphonyl and 2-(phenoxymethyl)pyrrolidin-1-yl)sulphonyl substitution at C5 position of isatin core exhibited better results compared to unsubstituted derivatives. According to the results of caspase inhibitory activity, compound20dshowed moderate inhibitory activity against caspase-3 and -7in vitrocompared to Ac-DEVD-CHO (IC50= 0.016 +/- 0.002 mu M). Among the studied compounds, some active inhibitors with IC(50s)in the range of 2.33-116.91 mu M were identified. The activity of compound20dwas rationalised by the molecular modelling studies exhibiting the additional van der Waals interaction of N-phenylacetamide substitution along with efficacious T-shaped pi-pi and pi-cation interactions. The introduction of compound20dwith good caspase inhibitory activity will help researchers to find more potent agents.
引用
收藏
页码:1674 / 1684
页数:11
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