Calderón Félix, Vidal-Mas Jaume, Burrows Jeremy, de la Rosa Juan Carlos, Jiménez-Díaz María Belén, Mulet Teresa, Prats Sara, Solana Jorge, Witty Michael, Gamo Francisco Javier, Fernández Esther
Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
Medicines for Malaria Venture (MMV) , 20, route de Pré-Bois-PO Box 1826, 1215 Geneva 15, Switzerland.
ACS Med Chem Lett. 2012 Feb 9;3(5):373-7. doi: 10.1021/ml300008j. eCollection 2012 May 10.
From the 13 533 chemical structures published by GlaxoSmithKline in 2010, we identified 47 quality starting points for lead optimization. One of the most promising hits was the TCMDC-139046, a molecule presenting an indoline core, which is well-known for its anxiolytic properties by interacting with serotonin antagonist receptors 5-HT2. The inhibition of this target will complicate the clinical development of these compounds as antimalarials. Herein, we present the antimalarial profile of this series and our efforts to avoid interaction with this receptor, while maintaining a good antiparasitic potency. By using a double-divergent structure-activity relationship analysis, we have obtained a novel lead compound harboring an indoline core.
从葛兰素史克公司2010年公布的13533种化学结构中，我们确定了47个用于先导优化的优质起始点。最有前景的命中化合物之一是TCMDC-139046，它是一种具有吲哚啉核心的分子，因其通过与5-羟色胺拮抗剂受体5-HT2相互作用而具有抗焦虑特性而闻名。抑制该靶点会使这些化合物作为抗疟药的临床开发变得复杂。在此，我们展示了该系列的抗疟活性概况以及我们在保持良好抗寄生虫效力的同时避免与该受体相互作用的努力。通过双发散构效关系分析，我们获得了一种含有吲哚啉核心的新型先导化合物。
