Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France; Sorbonne Université, CNRS, FR2424, Plateforme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, 29680, Roscoff Cedex, France.
Chem Biol Interact. 2021 Jul 1;343:109478. doi: 10.1016/j.cbi.2021.109478. Epub 2021 Apr 25.
7-Azaindole has been labelled a privileged scaffold for the design of new potent inhibitors of protein kinases. In this paper, we determined the inhibition profiles of novel mono- and disubstituted derivatives of 7-azaindole-coumaranone hybrids on various disease-related protein kinases. Eight hit compounds were identified, including a potent Haspin inhibitor with an IC value of 0.15 μM. An interesting observation was that all active monosubstituted compounds displayed dual inhibition for Haspin and GSK-3β, while disubstituted derivatives inhibited GSK-3β and LmCK1 from Leishmania major parasite. Analyses of structure activity relationships (SARs) also revealed that mono-substitution with para-fluorobenzyloxy ring produced an equipotent inhibition of Haspin and GSK-3β. Haspin and GSK-3β are relevant targets for developing new anticancer agents while LmCK1 is an innovative target for leishmanicidal drugs. Novel compounds reported in this paper constitute promising starting points for the development of new anticancer and leishmanicidal drugs.
7-氮茚已被标记为设计新型有效蛋白激酶抑制剂的优势骨架。在本文中，我们确定了新型单取代和双取代 7-氮茚-香豆素杂合体衍生物对各种与疾病相关的蛋白激酶的抑制谱。鉴定出了 8 种命中化合物，其中包括具有 IC 值为 0.15 μM 的强效 Haspin 抑制剂。一个有趣的观察结果是，所有活性的单取代化合物均表现出对 Haspin 和 GSK-3β 的双重抑制，而双取代衍生物则抑制了来自利什曼原虫寄生虫的 GSK-3β 和 LmCK1。对构效关系 (SAR) 的分析还表明，用对氟苯甲氧基环进行单取代可产生对 Haspin 和 GSK-3β 的等效抑制。Haspin 和 GSK-3β 是开发新型抗癌药物的相关靶点，而 LmCK1 是新型杀利什曼原虫药物的靶点。本文报道的新型化合物为开发新型抗癌和杀利什曼原虫药物提供了有希望的起点。
