Almolhim Hanan, Ding Sha, Butler Joshua H, Bremers Emily K, Butschek Grant J, Slebodnick Carla, Merino Emilio F, Rizopoulos Zaira, Totrov Maxim, Cassera Maria B, Carlier Paul R
Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, 1040 Drillfield Drive, Blacksburg, Virginia 24061, United States.
Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases, University of Georgia, 120 Green Street, Athens, Georgia 30602, United States.
ACS Med Chem Lett. 2022 Feb 24;13(3):371-376. doi: 10.1021/acsmedchemlett.1c00697. eCollection 2022 Mar 10.
The tetrahydro-β-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138 () and cipargamin ()). Similarity searching of a publicly disclosed collection of antimalarial hits for molecules resembling drew our attention to N2-acyl tetrahydro-β-carboline GNF-Pf-5009 ((±)-). Compound purchase, "analog by catalog", and independent synthesis of hits indicated the benzofuran-2-yl amide portion was required for efficacy against . Preparation of pure enantiomers demonstrated the pharmacological superiority of ()-. Synthesis and evaluation of D- and F-ring substitution variants and benzofuran isosteres indicated a clear structure-activity relationship. Ultimately ()- was tested in -infected mice; unfavorable physicochemical properties may be responsible for the lack of oral efficacy.
四氢-β-咔啉骨架已被证明是发现抗疟药物的肥沃土壤（例如，MMV008138 () 和环吡氯胍 ()）。对公开披露的抗疟活性化合物库进行相似性搜索，寻找与 相似的分子，这使我们将注意力集中到了N2-酰基四氢-β-咔啉GNF-Pf-5009（(±)-）上。化合物购买、“按目录找类似物”以及对活性化合物的独立合成表明，苯并呋喃-2-基酰胺部分对于抗 疗效是必需的。制备纯对映体证明了()- 的药理学优势。对D环和F环取代变体以及苯并呋喃生物电子等排体的合成和评估表明了明确的构效关系。最终，()- 在感染 的小鼠中进行了测试；不良的物理化学性质可能是口服疗效不佳的原因。
