Woodring Jennifer L, Behera Ranjan, Sharma Amrita, Wiedeman Justin, Patel Gautam, Singh Baljinder, Guyett Paul, Amata Emanuele, Erath Jessey, Roncal Norma, Penn Erica, Leed Susan E, Rodriguez Ana, Sciotti Richard J, Mensa-Wilmot Kojo, Pollastri Michael P
Department of Chemistry & Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
Department of Cellular Biology, Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, United States.
ACS Med Chem Lett. 2018 Sep 4;9(10):996-1001. doi: 10.1021/acsmedchemlett.8b00245. eCollection 2018 Oct 11.
Discovery of new chemotherapeutic lead agents can be accelerated by optimizing chemotypes proven to be effective in other diseases to act against parasites. One such medicinal chemistry campaign has focused on optimizing the anilinoquinazoline drug lapatinib () and the alkynyl thieno[3,2-]pyrimidine hit GW837016X (NEU-391, ) into leads for antitrypanosome drugs. We now report the structure-activity relationship studies of and its analogs against , which causes human African trypanosomiasis (HAT). The series was also tested against , , and . In each case, potent antiparasitic hits with acceptable toxicity margins over mammalian HepG2 and NIH3T3 cell lines were identified. In a mouse model of HAT, extended life of treated mice by 50%, compared to untreated controls. At the cellular level, inhibited mitosis and cytokinesis in . Thus, the alkynylthieno[3,2-]pyrimidine chemotype is an advanced hit worthy of further optimization as a potential chemotherapeutic agent for HAT.
通过优化已被证明对其他疾病有效的化学类型以对抗寄生虫，可以加速新型化疗先导药物的发现。一项这样的药物化学研究致力于将苯胺基喹唑啉药物拉帕替尼（）和炔基噻吩并[3,2 - ]嘧啶先导化合物GW837016X（NEU - 391，）优化为抗锥虫药物的先导物。我们现在报告了 及其类似物针对导致人类非洲锥虫病（HAT）的 的构效关系研究。该系列还针对 、 和 进行了测试。在每种情况下，都鉴定出了对哺乳动物HepG2和NIH3T3细胞系具有可接受毒性范围的强效抗寄生虫先导物。在HAT小鼠模型中，与未治疗的对照组相比， 使治疗小鼠的寿命延长了50%。在细胞水平上， 抑制了 中的有丝分裂和胞质分裂。因此，炔基噻吩并[3,2 - ]嘧啶化学类型是一个值得进一步优化的先进先导物，可作为HAT的潜在化疗药物。
