Corrigendum: Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors
摘要：
A library of arylidenefuropyridinediones was discovered as potent inhibitors ofLeishmania donovaniTopoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50values. This molecular library was designedviaintuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human topoisomerase 1 (HTop1) andLeishmania donovanitopoisomerase 1(LdTop1). The most active compound4displayed no cytotoxicity against normal mammalian COS7 cell line (~100 fold less inhibition at the EC50). Similar to camptothecin,4interacted with free LdTop1 as observed in the preincubation DNA relaxation inhibition experiment. It also displayed anti-protozoal activity againstLeishmania donovanipromastigote. Crystal structure investigation of4and its molecular modelling with LdTop1 revealed putative binding sites in the enzyme that could be harnessed to generate molecules with better potency.
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DOI：
10.1038/srep26603
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年份：
2016
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