Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):1674-1684. doi: 10.1080/14756366.2020.1809388.
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, compound showed moderate inhibitory activity against caspase-3 and -7 compared to Ac-DEVD-CHO (IC = 0.016 ± 0.002 μM). Among the studied compounds, some active inhibitors with IC in the range of 2.33-116.91 μM were identified. The activity of compound was rationalised by the molecular modelling studies exhibiting the additional van der Waals interaction of N-phenylacetamide substitution along with efficacious T-shaped π-π and pi-cation interactions. The introduction of compound with good caspase inhibitory activity will help researchers to find more potent agents.
摘要 在本文中，设计、合成并评价了一系列新型的靛红磺酰胺类衍生物作为半胱天冬酶抑制剂。与未取代的衍生物相比，在靛红核心 C5 位置含有 1-(吡咯烷基)磺酰基和 2-(苯氧甲基)吡咯烷-1-基)磺酰基取代的化合物表现出更好的结果。根据半胱天冬酶抑制活性的结果，化合物 对 caspase-3 和 -7 的抑制活性与 Ac-DEVD-CHO（IC=0.016±0.002μM）相比表现出中等抑制活性。在所研究的化合物中，确定了一些具有 2.33-116.91μM 范围内的 IC 的活性抑制剂。通过分子建模研究，化合物 的活性得到了合理的解释，表明 N-苯乙酰胺取代物的额外范德华相互作用以及有效的 T 型 π-π 和 pi-阳离子相互作用。引入具有良好半胱天冬酶抑制活性的化合物将有助于研究人员发现更有效的药物。
