Mathew Jopaul, Ding Sha, Kunz Kevin A, Stacy Emily E, Butler Joshua H, Haney Reagan S, Merino Emilio F, Butschek Grant J, 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 23;13(3):365-370. doi: 10.1021/acsmedchemlett.1c00663. eCollection 2022 Mar 10.
Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite . Interestingly, , a minor byproduct of these syntheses, proved to be potent against and was orally efficacious (40 mg/kg) in an mouse model of malaria.
使用源自抗疟药物MMV008138的药效团对公开可用的抗疟命中数据库进行虚拟配体筛选，确定了一种四氢-β-咔啉酰胺TCMDC-140230值得探索。合成了该结构的所有四种立体异构体，但均未有效抑制疟原虫的生长。有趣的是，这些合成反应的一种次要副产物被证明对疟原虫有效，并且在疟疾小鼠模型中口服有效（40mg/kg）。
