Heidebrecht Richard W, Mulrooney Carol, Austin Christopher P, Barker Robert H, Beaudoin Jennifer A, Cheng Ken Chih-Chien, Comer Eamon, Dandapani Sivaraman, Dick Justin, Duvall Jeremy R, Ekland Eric H, Fidock David A, Fitzgerald Mark E, Foley Michael, Guha Rajarshi, Hinkson Paul, Kramer Martin, Lukens Amanda K, Masi Daniela, Marcaurelle Lisa A, Su Xin-Zhuan, Thomas Craig J, Weïwer Michel, Wiegand Roger C, Wirth Dyann, Xia Menghang, Yuan Jing, Zhao Jinghua, Palmer Michelle, Munoz Benito, Schreiber Stuart
ACS Med Chem Lett. 2012 Feb 9;3(2):112-117. doi: 10.1021/ml200244k. Epub 2011 Dec 22.
Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure-activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.
在此，我们描述了一种新型抗疟药的发现过程，该过程采用对恶性疟原虫无性血液期寄生虫进行表型筛选的方法。对通过多样性导向合成（DOS）创建的新型化合物库进行筛选，得到了最初的活性化合物。构效关系指导了具有更高效力和水溶性的化合物的合成，从而产生了一种对寄生虫无性血液期生长具有亚纳摩尔抑制作用的抑制剂。优化后的化合物27在红细胞裂解和HepG2检测中具有出色的脱靶活性谱，并且在人血浆中稳定。该化合物可通过分子文库探针生产中心网络（MLPCN）获得，编号为ML238。
